Novel aminal compounds and their derivatives can open potassium channels and are useful for treating a variety of medical conditions.
Potassium channels play an important role in regulating cell membrane excitability. When the potassium channels open, changes in the electrical potential across the cell membrane occur and result in a more polarized state. A number of diseases or conditions may be treated with therapeutic agents that open potassium channels; see for example (Lawson, Pharmacol. Ther., v. 70, pp. 39-63 (1996)); (Gehlert et al., Prog. Neuro-Psychopharmacol and Biol. Psychiat., v. 18, pp. 1093-1102 (1994)); (Gopalakrishnan et al., Drug Development Research, v. 28, pp. 95-127 (1993)); (Freedman et al., The Neuroscientist, v. 2, pp. 145-152 (1996)); (Nurse et al., Br. J. Urol., v. 68 pp. 27-31 (1991)); (Howe et al., J. Pharmacol. Exp. Ther., v. 274 pp. 884-890 (1995)); (Spanswick et al., Nature, v. 390 pp. 521-25 (Dec. 4, 1997)); (Dompeling Vasa. Supplementum (1992) 3434); (WO9932495); (Grover, J Mol Cell Cardiol. (2000) 32, 677); and (Buchheit, Pulmonary Pharmacology and Therapeutics (1999) 12, 103). Such diseases or conditions include asthma, epilepsy, male sexual dysfunction female sexual dysfunction, pain, bladder overactivity, stroke, diseases associated with decreased skeletal blood flow such as Raynaud""s phenomenon and intermittent claudication, eating disorders, functional bowel disorders, neurodegeneration, benign prostatic hyperplasia (BPH), dysmenorrhea, premature labor, alopecia, cardioprotection, coronary artery disease, angina and ischemia.
Bladder overactivity is a condition associated with the spontaneous, uncontrolled contractions of the bladder smooth muscle. Bladder overactivity thus is associated with sensations of urgency, urinary incontinence, pollakiuria, bladder instability, nocturia, bladder hyerreflexia, and enuresis (Resnick, The Lancet (1995) 346, 94-99; Hampel, Urology (1997) 50 (Suppl 6A), 4-14; Bosch, BJU International (1999) 83 (Suppl 2), 79). Potassium channel openers (KCOs) act as smooth muscle relaxants. Because bladder overactivity and urinary incontinence can result from the spontaneous, uncontrolled contractions of the smooth muscle of the bladder, the ability of potassium channel openers to hyperpolarize bladder cells and relax bladder smooth muscle may provide a method to ameliorate or prevent bladder overactivity, pollakiuria, bladder instability, nocturia, bladder hyperreflexia, urinary incontinence, and enuresis (Andersson, Urology (1997) 50 (Suppl 6A), 74-84; Lawson, Pharmacol. Ther., (1996) 70, 39-63; Nurse., Br. J. Urol., (1991) 68, 27-31; Howe, J. Pharmacol. Exp. Ther., (1995) 274, 884-890; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127).
The irritative symptoms of BPH (urgency, frequency, nocturia and urge incontinence) have been shown to be correlated to bladder instability (Pandita, The J. of Urology (1999) 162, 943). Therefore the ability of potassium channel openers to hyperpolarize bladder cells and relax bladder smooth muscle may provide a method to ameliorate or prevent the symptoms associated with BPH. (Andersson, Prostate (1997) 30: 202-215).
The excitability of corpus cavernosum smooth muscle cells is important in the male erectile process. The relaxation of corporal smooth muscle cells allows arterial blood to build up under pressure in the erectile tissue of the penis leading to erection (Andersson, Pharmacological Reviews (1993) 45, 253). Potassium channels play a significant role in modulating human corporal smooth muscle tone, and thus, erectile capacity. By patch clamp technique, potassium channels have been characterized in human corporal smooth muscle cells (Lee, Int. J. Impot. Res. (1999) 11(4), 179-188). Potassium channel openers are smooth muscle relaxants and have been shown to relax corpus cavernosal smooth muscle and induce erections (Andersson, Pharmacological Reviews (1993) 45, 253; Lawson, Pharmacol. Ther., (1996) 70, 39-63, Vick, J. Urol. (2000) 163: 202). Potassium channel openers therefore may have utility in the treatment of male sexual dysfunctions such as male erectile dysfunction, impotence and premature ejaculation.
The sexual response in women is classified into four stages: excitement, plateau, orgasm and resolution. Sexual arousal and excitement increase blood flow to the genital area, and lubrication of the vagina as a result of plasma transudation. Topical application of KCOs like minoxidil and nicorandil have been shown to increase clitoral blood flow (Kim et al., J. Urol. (2000) 163 (4): 240). KCOs may be effective for the treatment of female sexual dysfunction including clitoral erectile insufficiency, vaginismus and vaginal engorgement (Goldstein and Berman., Int.J. Impotence Res. (1998) 10:S84-S90), as KCOs can increase blood flow to female sexual organs.
Potassium channel openers may have utility as tocolytic agents to inhibit uterine contractions to delay or prevent premature parturition in individuals or to slow or arrest delivery for brief periods to undertake other therapeutic measures (Sanborn, Semin. Perinatol. (1995) 19, 31-40; Morrison, Am. J. Obstet. Gynecol. (1993) 169(5), 1277-85). Potassium channel openers also inhibit contractile responses of human uterus and intrauterine vasculature. This combined effect would suggest the potential use of KCOs for dysmenhorrea (Kostrzewska, Acta Obstet. Gynecol. Scand. (1996) 75(10), 886-91). Potassium channel openers relax uterine smooth muscle and intrauterine vasculature and therefore may have utility in the treatment of premature labor and dysmenorrhoea (Lawson, Pharmacol. Ther., (1996) 70, 39-63).
Potassium channel openers relax gastrointestinal smooth tissues and therefore may be useful in the treatment of functional bowel disorders such as irritable bowel syndrome (Lawson, Pharmacol. Ther., (1996) 70, 39-63).
Potassium channel openers relax airway smooth muscle and induce bronchodilation. Therefore potassium channel openers may be useful in the treatment of asthma and airways hyperreactivity (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Buchheit, Pulmonary Pharmacology and Therapeutics (1999) 12, 103; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127).
Neuronal hyperpolarization can produce analgesic effects. The opening of potassium channels by potassium channel openers and resultant hyperpolarization in the membrane of target neurons is a key mechanism in the effect of opioids. The peripheral antinociceptive effect of morphine results from activation of ATP-sensitive potassium channels, which causes hyperpolarization of peripheral terminals of primary afferents, leading to a decrease in action potential generation (Rodrigues, Br J Pharmacol (2000) 129(1), 110-4). Opening of KATP channels by potassium channel openers plays an important role in the antinociception mediated by alpha-2 adrenoceptors and mu opioid receptors. KCOs can potentiate the analgesic action of both morphine and dexmedetomidine via an activation of KATP channels at the spinal cord level (Vergoni, Life Sci. (1992) 50(16), PL135-8; Asano, Anesth. Analg. (2000) 90(5), 1146-51). Thus, potassium channel openers can hyperpolarize neuronal cells and have shown analgesic effects. Potassium channel openers therefore may be useful as analgesics in the treatment of various pain states including but not limited to migraine and dyspareunia (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127; Gehlert, Prog. Neuro-Psychopharmacol. and Biol. Psychiat., (1994) 18, 1093-1102).
Epilepsy results from the propagation of nonphysiologic electrical impulses. Potassium channel openers hyperpolarize neuronal cells and lead to a decrease in cellular excitability and have demonstrated antiepileptic effects. Therefore potassium channel openers may be useful in the treatment of epilepsy (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127; Gehlert, Prog. Neuro-Psychopharmacol. and Biol. Psychiat., (1994) 18, 1093-1102).
Neuronal cell depolarization can lead to excitotoxicity and neuronal cell death. When this occurs as a result of acute ischemic conditions, it can lead to stroke. Long term neurodegeneration can bring about conditions such as Alzheimer""s and Parkinson""s diseases. Potassium channel openers can hyperpolarize neuronal cells and lead to a decrease in cellular excitability. Activation of potassium channels has been shown to enhance neuronal survival. Therefore potassium channel openers may have utility as neuroprotectants in the treatment of neurodegenerative conditions and diseases such as cerebral ischemia, stroke, Alzheimer""s disease and Parkinson""s disease (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127; Gehlert, Prog. Neuro-Psychopharmacol and Biol. Psychiat., (1994) 18, 1093-1102; Freedman, The Neuroscientist (1996) 2, 145).
Potassium channel openers may have utility in the treatment of diseases or conditions associated with decreased skeletal muscle blood flow such as Raynaud""s syndrome and intermittent claudication (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127; Dompeling Vasa. Supplementum (1992) 3434; and WO9932495).
Potassium channel openers may be useful in the treatment of eating disorders such as obesity (Spanswick, Nature, (1997) 390, 521-25; Freedman, The Neuroscientist (1996) 2, 145).
Potassium channel openers have been shown to promote hair growth therefore potassium channel openers have utility in the treatment of hair loss and baldness also known as alopecia (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127).
Potassium channel openers possess cardioprotective effects against myocardial injury during ischemia and reperfusion (Garlid, Circ. Res. (1997) 81(6), 1072-82). Therefore, potassium channel openers may be useful in the treatment of heart diseases (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Grover, J. Mol. Cell Cardiol. (2000) 32, 677).
Potassium channel openers, by hyperpolarization of smooth muscle membranes, can exert vasodilation of the collateral circulation of the coronary vasculature leading to increase blood flow to ischemic areas and could be useful for the coronary artery disease (Lawson, Pharmacol. Ther., (1996) 70, 39-63, Gopalakrishnan, Drug Development Research, (1993) 28, 95-127).
U.S. Pat. No. 3,636,105 discloses a group of 1-fluoroacetylamino-2,2,2-trichloroethyl urea rodenticide agents. U.S. Pat. No. 4,146,646 discloses a group of bis-amide fungicide agents. U.S. Pat. No. 5,140,031 and U.S. Pat. No. 5,278,169 disclose a group of cyanoguanidine cardiovascular agents. U.S. Pat. No. 4,057,636 discloses a group of pyridylcyanoguanidine hypotensive agents. U.S. Pat. No. 5,547,966 discloses a group of urea, thiourea, and cyanoguanidine agents for treating ischemia. ZA 695324 discloses a group of thioureas useful as insecticide, acaricidal, and rodenticide agents. WO 92/04045 discloses a group of carbamate cholecystokinin receptor antagonists. WO 97/14417 discloses a group of peptide mimetic agents useful as fibrinogen receptor antagonists. WO 98/57940 discloses a group of oxazolidinone and imidazolidinone agents useful as xcex11A receptor antagonists. WO 99/28291 discloses a group of bis(hydroxyureas) useful as inhibitors of 5-lipoxygenase.
Compounds of the present invention are novel, hyperpolarize cell membranes, open potassium channels, relax smooth muscle cells, inhibit bladder contractions and may be useful for treating diseases that can be ameliorated by opening potassium channels.
In its principal embodiment, the present invention discloses compounds having formula I: 
or a pharmaceutically acceptable salt, amide, ester or prodrug thereof wherein,
X is selected from O, S, CHCN, C(CN)2, CHNO2 and NR8;
R8 is selected from hydrogen, alkoxy, alkyl, alkylsulfonyl, arylalkoxy, aryloxy, arylsulfonyl, cyano, haloalkylsulfonyl, heterocyclealkoxy, heterocycleoxy, hydroxy, nitro, and sulfamyl;
R1 is selected from aryl, arylalkyl, heterocycle, and heterocyclealkyl;
R2 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonyl(halo)alkyl, alkoxy(halo)alkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyl(halo)alkyl, alkylcarbonyloxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkylthioalkyl, alkynyl, amido, amidoalkyl, aryl, arylalkoxyalkyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylalkyl, arylcarbonyl, arylcarbonylalkyl, arylcarbonyloxyalkyl, aryl(halo)alkyl, aryloxyalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, arylalkylthioalkyl, arylsulfonylalkyl, carboxy, carboxyalkyl, carboxy(halo)alkyl, cyanoalkyl, cyano(halo)alkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkoxyalkyl, cycloalkylalkyl, cycloalkylcarbonyl, cycloalkyloxyalkyl, cycloalkylalkylthioalkyl, formyl, haloalkenyl, haloalkyl, haloalkylcarbonyl, haloalkynyl, heterocycle, heterocyclealkoxyalkyl, heterocyclealkyl, heterocyclecarbonyl, heterocycleoxyalkyl, heterocyclealkylthioalkyl, hydroxyalkyl, mercaptoalkyl, sulfamylalkyl, sulfamyl(halo)alkyl, and (NR9R10)alkyl wherein R9 and R10 are independently selected from hydrogen, alkyl, akylcarbonyl, aryl, arylalkyl, arylcarbonyl, formyl, and S(O)2R11, wherein R11 is selected from alkyl, aryl, and arylalkyl;
R3 is selected from alkyl, aryl, arylalkyl, heterocycle, and heterocyclealkyl;
R4 is hydrogen; or
R4 and R1 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, indolinyl and isoindolinyl wherein benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, indolinyl and isoindolinyl are optionally substituted with 1, 2, or 3 substituents independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfinyl, alkylsulfonyl, alkynyl, arylalkoxycarbonyl, cyano, halogen, haloalkyl, haloalkoxy, nitro, sulfamyl, and xe2x80x94NRARB wherein RA and RB are independently selected from hydrogen, alkyl, alkylcarbonyl and formyl;
R5 is selected from hydrogen, alkyl and OR12;
R12 is selected from hydrogen, alkyl and arylalkyl; or
R5 and R4 taken together form an alkylene bridge of 2-3 carbons;
R6 is hydrogen; or
R6 and R5 taken together form an alkylene bridge of 2-3 carbons; or
R6 taken together with the nitrogen atom to which it is attached and R3 taken together with the carbon atom to which it is attached, together form a heterocycle selected from 1-isoindolinonyl and 1-isoquinolinonyl wherein 1-isoindolinonyl and 1-isoquinolinonyl are optionally substituted with 1, 2, or 3 substituents selected from alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfinyl, alkylsulfonyl, alkynyl, arylalkoxycarbonyl, cyano, halogen, haloalkyl, haloalkoxy, nitro, oxo, sulfamyl, and xe2x80x94NRARB wherein RA and RB are independently selected from hydrogen, alkyl, alkylcarbonyl and formyl; and
R7 is selected from hydrogen, haloalkyl and lower alkyl; or
R7 and R2 taken together with the carbon atom to which they are attached, together form a 5 or 6 membered carbocyclic ring wherein the 5 or 6 membered carbocyclic ring is optionally substituted with 1 or 2 substituents independently selected from alkenyl, alkoxy, alkyl, alkynyl, halogen, haloalkoxy, and haloalkyl;
provided that when X is O; R2 is xe2x80x94CCl3; R3 is alkyl or phenyl; and R4, R5, R6, and R7 are hydrogen; then R1 is other than phenyl.
All patents, patent applications, and literature references cited in the specification are herein incorporated by reference in their entirety. In the case of inconsistencies, the present disclosure, including definitions, will prevail.
It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and/or methods of use of the invention, may be made without departing from the spirit and scope thereof.
In its principal embodiment, the present invention discloses compounds having formula I: 
or a pharmaceutically acceptable salt, amide, ester or prodrug thereof wherein,
X is selected from O, S, CHCN, C(CN)2, CHNO2 and NR8;
R8 is selected from hydrogen, alkoxy, alkyl, alkylsulfonyl, arylalkoxy, aryloxy, arylsulfonyl, cyano, haloalkylsulfonyl, heterocyclealkoxy, heterocycleoxy, hydroxy, nitro, and sulfamyl;
R1 is selected from aryl, arylalkyl, heterocycle, and heterocyclealkyl;
R2 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonyl(halo)alkyl, alkoxy(halo)alkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyl(halo)alkyl, alkylcarbonyloxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkylthioalkyl, alkynyl, amido, amidoalkyl, aryl, arylalkoxyalkyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylalkyl, arylcarbonyl, arylcarbonylalkyl, arylcarbonyloxyalkyl, aryl(halo)alkyl, aryloxyalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, arylalkylthioalkyl, arylsulfonylalkyl, carboxy, carboxyalkyl, carboxy(halo)alkyl, cyanoalkyl, cyano(halo)alkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkoxyalkyl, cycloalkylalkyl, cycloalkylcarbonyl, cycloalkyloxyalkyl, cycloalkylalkylthioalkyl, formyl, haloalkenyl, haloalkyl, haloalkylcarbonyl, haloalkynyl, heterocycle, heterocyclealkoxyalkyl, heterocyclealkyl, heterocyclecarbonyl, heterocycleoxyalkyl, heterocyclealkylthioalkyl, hydroxyalkyl, mercaptoalkyl, sulfamylalkyl, sulfamyl(halo)alkyl, and (NR9R10)alkyl wherein R9 and R10 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl, formyl, and S(O)2R11, wherein R11 is selected from alkyl, aryl, and arylalkyl;
R3 is selected from alkyl, aryl, arylalkyl, heterocycle, and heterocyclealkyl;
R4 is hydrogen; or
R4 and R1 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, indolinyl and isoindolinyl wherein benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, indolinyl and isoindolinyl are optionally substituted with 1, 2, or 3 substituents independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfinyl, alkylsulfonyl, alkynyl, arylalkoxycarbonyl, cyano, halogen, haloalkyl, haloalkoxy, nitro, sulfamyl, and xe2x80x94NRARB wherein RA and RB are independently selected from hydrogen, alkyl, alkylcarbonyl and formyl;
R5 is selected from hydrogen, alkyl and OR12;
R 12 is selected from hydrogen, alkyl and arylalkyl; or
R5 and R4 taken together form an alkylene bridge of 2-3 carbons;
R6 is hydrogen; or
R6 and R5 taken together form an alkylene bridge of 2-3 carbons; or
R6 taken together with the nitrogen atom to which it is attached and R3 taken together with the carbon atom to which it is attached, together form a heterocycle selected from 1-isoindolinonyl and 1-isoquinolinonyl wherein 1-isoindolinonyl and 1-isoquinolinonyl are optionally substituted with 1, 2, or 3 substituents selected from alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfinyl, alkylsulfonyl, alkynyl, arylalkoxycarbonyl, cyano, halogen, haloalkyl, haloalkoxy, nitro, oxo, sulfamyl, and xe2x80x94NRARB wherein RA and RB are independently selected from hydrogen, alkyl, alkylcarbonyl and formyl; and
R7 is selected from hydrogen, haloalkyl and lower alkyl; or
R7 and R2 taken together with the carbon atom to which they are attached, together form a 5 or 6 membered carbocyclic ring wherein the 5 or 6 membered carbocyclic ring is optionally substituted with 1 or 2 substituents independently selected from alkenyl, alkoxy, alkyl, alkynyl, halogen, haloalkoxy, and haloalkyl;
provided that when X is O; R2 is xe2x80x94CCl3; R3 is alkyl or phenyl; and R4, R5, R6, and R7 are hydrogen; then R1 is other than phenyl.
In another embodiment of the present invention, compounds have formula I wherein X is selected from O, S, CHCN, C(CN)2, CHNO2, and NR8; R8 is selected from alkoxy, alkylsulfonyl, arylalkoxy, arylsulfonyl, cyano, haloalkylsulfonyl, hydroxy, and nitro; R1 is selected from the aryl, arylalkyl, heterocycle, and heterocyclealkyl; R2 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylsulfonylalkyl, alkylthioalkyl, aryl, arylalkyl, arylsulfonylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkylcarbonyl, heterocycle, heterocyclealkyl, hydroxyalkyl, sulfamylalkyl, and (NR9R10)alkyl; R3 is selected from aryl, arylalkyl, and heterocycle; R4 is hydrogen; or R4 and R1 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from benzimidazolyl and indolyl wherein benzimidazolyl and indolyl are optionally substituted with 1 or 2 substituents independently selected from alkoxy, alkyl, halo, haloalkyl, and haloalkoxy; R5 is selected from hydrogen and alkyl; or R5 and R4 taken together form an alkylene bridge of 2-3 carbons; R6 is hydrogen; or R6 and R5 taken together form an alkylene bridge of 2-3 carbons; or R6 taken together with the nitrogen atom to which it is attached and R3 taken together with the carbon atom to which it is attached, together form a heterocycle selected from 1-isoindolinonyl and 1-isoquinolinonyl wherein 1-isoindolinonyl and 1-isoquinolinonyl are optionally substituted with 1 or 2 substituents selected from alkoxy, alkyl, halo, haloalkyl, and haloalkoxy; R7 is selected from hydrogen, haloalkyl, and lower alkyl; or R7 and R2 taken together with the carbon atom to which they are attached, together form a 5 or 6 membered carbocyclic ring wherein the 5 or 6 membered carbocyclic ring is optionally substituted with 1 or 2 substituents independently selected from alkyl, halo, haloalkoxy, and haloalkyl; and R9 and R10 are as defined in formulaI.
In another embodiment of the present invention, compounds have formula I wherein X is selected from O, S, CHCN, C(CN)2, CHNO2, and NR8; R8 is selected from alkoxy, alkylsulfonyl, haloalkylsulfonyl, cyano, hydroxy, nitro, arylalkoxy wherein the aryl portion of arylalkoxy is phenyl, and arylsulfonyl wherein the aryl portion of arylsulfonyl is phenyl; R1 is selected from heterocycle and aryl wherein heterocycle is selected from pyridinyl, pyrimidinyl and quinolinyl wherein pyridinyl, pyrimidinyl and quinolinyl are optionally substituted with 1, 2, or 3 substituents independently selected from alkoxy, alkyl, halo, haloalkyl, nitro, phenylsulfonyl and sulfamyl, and wherein aryl is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from alkoxy, alkyl, halo, haloalkyl, nitro, phenylsulfonyl, and sulfamyl; R2 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylsulfonylalkyl, aryl wherein aryl is phenyl, arylalkyl wherein the aryl portion of arylalkyl is phenyl, arylsulfonylalkyl wherein the aryl portion of arylsulfonylalkyl is phenyl, cyanoalkyl, cycloalkenylalkyl, cycloalkyl, haloalkyl, haloalkylcarbonyl, hydroxyalkyl, sulfamylalkyl, (NR9R10)alkyl and heterocycle wherein heterocycle is selected from 1,3-dioxanyl, pyrrolidinyl and thienyl; R3 is selected from aryl wherein aryl is phenyl and arylalkyl wherein the aryl portion of arylalkyl is phenyl; R4 is hydrogen; or R4 and R1 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from benzimidazolyl and indolyl wherein benzimidazolyl and indolyl are optionally substituted with 1 or 2 substituents independently selected from alkoxy, alkyl, halo, haloalkyl, and haloalkoxy; R5 is hydrogen; or R5 and R4 taken together form an alkylene bridge of 2-3 carbons; R6 is hydrogen; or R6 and R5 taken together form an alkylene bridge of 2-3 carbons; or R6 taken together with the nitrogen atom to which it is attached and R3 taken together with the carbon atom to which it is attached, together form a heterocycle selected from 1-isoindolinonyl and 1-isoquinolinonyl wherein 1-isoindolinonyl and 1-isoquinolinonyl are optionally substituted with 1 or 2 substituents selected from alkoxy, alkyl, halo, haloalkyl, and haloalkoxy; R7 is selected from hydrogen, haloalkyl, and lower alkyl; or R7 and R2 taken together with the carbon atom to which they are attached, together form a 5 or 6 membered carbocyclic ring wherein the 5 or 6 membered carbocyclic ring is optionally substituted with 1 or 2 substituents independently selected from alkyl, halo, haloalkoxy, and haloalkyl; and R9 and R10 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is selected from O, S, CHNO2, C(CN)2, and NR8; R8 is selected from arylsulfonyl, cyano, haloalkylsulfonyl, nitro and sulfamyl; R1 is selected from aryl, arylalkyl, heterocycle and heterocyclalkyl; R2 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkyl, alkylthioalkyl, aryl, arylalkyl, cyanoalkyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycle and (NR9R10) alkyl; R3 is selected from aryl and arylalkyl; R4 is hydrogen; R5 is selected from hydrogen and alkyl; or R5 and R4 taken together form an alkylene bridge of 2-3 carbons; R6 is hydrogen; R7 is hydrogen; and R9 and R10 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is selected from O, S, CHNO2, C(CN)2, and NR8; R8 is selected from arylsulfonyl wherein the aryl portion of arylsulfonyl is phenyl, cyano, haloalkylsulfonyl, nitro and sulfamyl; R1 is selected from aryl wherein aryl is phenyl, arylalkyl wherein the aryl portion of arylalkyl is phenyl, heterocycle wherein heterocycle is selected from quinolinyl, pyridinyl and pyrimidinyl, and heterocyclalkyl wherein the heterocycle portion of heterocyclealkyl is pyridinyl; R2 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkyl, alkylthioalkyl, aryl wherein aryl is phenyl, arylalkyl wherein the aryl portion of arylalkyl is phenyl, cyanoalkyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, (NR9R10)alkyl and heterocycle wherein heterocycle is selected from 1,3-dioxanyl, pyrrolidinyl and thienyl; R3 is selected from aryl wherein aryl is phenyl and arylalkyl wherein the aryl portion of arylalkyl is phenyl; R4 is hydrogen; R5 is selected from hydrogen and alkyl; or R5 and R4 taken together form an alkylene bridge of 2-3 carbons; R6 is hydrogen; R7 is hydrogen; and R9 and R10 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is NR8; R8 is cyano; R1 is selected from heterocycle and heterocyclealkyl; R3 is selected from heterocycle and heterocyclealkyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R2 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is NR8; R8 is cyano; R1 is selected from heterocycle and heterocyclealkyl; R2 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkyl, alkylthioalkyl, aryl, arylalkyl, cyanoalkyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycle and (NR9R10)alkyl; R3 is selected from heterocycle and heterocyclealkyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula I wherein X is NR8; R8 is cyano; R1 is heterocycle wherein heterocycle is pyridinyl; R2 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkyl, alkylthioalkyl, aryl wherein aryl is phenyl, arylalkyl wherein the aryl portion of arylalkyl is phenyl, cyanoalkyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, (NR9R10)alkyl and heterocycle wherein heterocycle is selected from the group consisting of 1,3-dioxanyl, pyrrolidinyl and thienyl; R3 is heterocycle wherein heterocycle is selected from the group consisting of furanyl, pyrazinyl, pyridinyl, pyrimidinyl and quinolinyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula I wherein X is NR8; R8 is cyano; R1 is selected from heterocycle and heterocyclealkyl; R3 is selected from aryl and arylalkyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R2 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is NR8; R8 is cyano; R1 is selected from heterocycle and heterocyclealkyl; R2 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkyl, alkylthioalkyl, aryl, arylalkyl, cyanoalkyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycle and (NR9R10)alkyl; R3 is selected from aryl and arylalkyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; and R9 and R10 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is NR8; R8 is cyano; R1 is heterocyclealkyl wherein the heterocycle portion of heterocyclealkyl is pyridinyl; R2 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkyl, alkylthioalkyl, aryl wherein aryl is phenyl, arylalkyl wherein the aryl portion of arylalkyl is phenyl, cyanoalkyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, (NR9R10)alkyl and heterocycle wherein heterocycle is selected from 1,3-dioxanyl, pyrrolidinyl and thienyl; R3 is aryl wherein aryl is phenyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R7, R9 and R10 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is NR8; R8 is cyano; R1 is heterocycle wherein the heterocycle is pyridinyl; R2 is selected alkyl and haloalkyl; R3 is aryl wherein aryl is phenyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula I wherein X is NR8; R8 is cyano; R1 is heterocycle wherein the heterocycle is pyridinyl; R2 is selected dichloroethyl; R3 is aryl wherein aryl is phenyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula I wherein X is NR8; R8 is cyano; R1 is heterocycle wherein the heterocycle pyridinyl which is optionally substituted with alkoxy, halo, and haloalkyl; R2 is selected dichloroethyl; R3 is aryl wherein aryl is phenyl which is optionally substituted with halo; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula I wherein X is NR8; R8 is cyano; R1 is heterocycle wherein the heterocycle is pyridinyl; R2 is selected alkyl and haloalkyl; R3 is heterocycle wherein wherein the heterocycle is pyridinyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula I wherein X is NR8; R8 is cyano; R1 is heterocycle wherein the heterocycle is pyridinyl; R2 is selected dichloroethyl; R3 is heterocycle wherein wherein the heterocycle is pyridinyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula I wherein X is NR8; R8 is cyano; R1 is heterocycle wherein the heterocycle is pyridinyl which is optionally substituted with alkoxy, halo, and haloalkyl; R2 is selected dichloroethyl; R3 is heterocycle wherein wherein the heterocycle is pyridinyl which is optionally substituted with alkoxy, halo, and haloalkyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula I wherein X is NR8; R8 is cyano; R1 is heterocycle wherein heterocycle is selected from quinolinyl and pyrimidinyl; R2 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkyl, alkylthioalkyl, aryl wherein aryl is phenyl, arylalkyl wherein the aryl portion of arylalkyl is phenyl, cyanoalkyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, (NR9R10)alkyl and heterocycle wherein heterocycle is selected from 1,3-dioxanyl, pyrrolidinyl and thienyl; R3 is aryl wherein aryl is phenyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; and R9 and R10 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is NR8; R8 is cyano; R1 is heterocycle wherein heterocycle is pyridinyl; R2 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkyl, alkylthioalkyl, aryl wherein aryl is phenyl, arylalkyl wherein the aryl portion of arylalkyl is phenyl, cyanoalkyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, (NR9R10)alkyl and heterocycle wherein heterocycle is selected from 1,3-dioxanyl, pyrrolidinyl and thienyl; R3 is aryl wherein aryl is phenyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; and R9 and R10 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is NR8; R8 is cyano; R1 is heterocycle; R2 is haloalkyl; R3 is aryl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula I wherein X is NR8; R8 is cyano; R1 is heterocycle wherein heterocycle is pyridinyl; R2 is haloalkyl; R3 is aryl wherein aryl is phenyl; R4 is hydrogen; R2 is hydrogen; R6 is hydrogen; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula I wherein X is NR8; R8 is cyano; R1 is heterocycle wherein heterocycle is 6-chloro-3-pyridinyl; R2 is haloalkyl; R3 is aryl wherein aryl is phenyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula I wherein X is NR8; R8 is cyano; R1 is heterocycle wherein heterocycle is 6-(trifluoromethyl)-3-pyridinyl; R2 is haloalkyl; R3 is aryl wherein aryl is phenyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula I wherein X is NR8; R8 is cyano; R1 is heterocycle wherein heterocycle is selected from quinolinyl, pyridinyl and pyrimidinyl; R2 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkyl, alkylthioalkyl, aryl wherein aryl is phenyl, arylalkyl wherein the aryl portion of arylalkyl is phenyl, cyanoalkyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, (NR9R10)alkyl and heterocycle wherein heterocycle is selected from 1,3-dioxanyl, pyrrolidinyl and thienyl; R3 is aryl wherein aryl is phenyl; R4 is hydrogen; R5 is alkyl; R6 is hydrogen; R7 is hydrogen; and R9 and R10 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is NR8; R8 is cyano; R1 is selected from heterocycle and heterocyclealkyl; R3 is alkyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R2 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is NR8; R8 is cyano; R1 is selected from aryl and arylalkyl; R3 is selected from heterocycle and heterocyclealkyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R2 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is NR8; R8 is cyano; R1 is selected from aryl and arylalkyl; R3 is selected from aryl and arylalkyl; R4 is hydrogen; R5 is hydrogen; and R6 is hydrogen; and R2 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is NR8; R8 is cyano; R1 is selected from aryl and arylalkyl; R2 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkyl, alkylthioalkyl, aryl, arylalkyl, cyanoalkyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycle and (NR9R10)alkyl; R3 is selected from aryl and arylalkyl; R4 is hydrogen R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; and R9 and R10 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is NR8; R8 is cyano; R1 is arylalkyl wherein the aryl portion of arylalkyl is phenyl; R2 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkyl, alkylthioalkyl, aryl wherein aryl is phenyl, arylalkyl wherein the aryl portion of arylalkyl is phenyl, cyanoalkyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, (NR9R10)alkyl and heterocycle wherein heterocycle is selected from 1,3-dioxanyl, pyrrolidinyl and thienyl; R3 is aryl wherein aryl is phenyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; and R9 and R10 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is NR8; R5 is cyano; R1 is aryl wherein aryl is phenyl; R2 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkyl, alkylthioalkyl, aryl wherein aryl is phenyl, arylalkyl wherein the aryl portion of arylalkyl is phenyl, cyanoalkyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, (NR9R10)alkyl and heterocycle wherein heterocycle is selected from 1,3-dioxanyl, pyrrolidinyl and thienyl; R3 is aryl wherein aryl is phenyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; and R9 and R10 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is NR8; R8 is cyano; R1 is selected from aryl and arylalkyl; R3 is alkyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R2 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is NR8; R8 is selected from hydrogen, alkoxy, alkyl, alkylsulfonyl, arylalkoxy, aryloxy, arylsulfonyl, haloalkylsulfonyl, heterocyclealkoxy, heterocycleoxy, hydroxy, nitro, and sulfamyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R1, R2, R3 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is NR8; R8 is nitro; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R1, R2, R3 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is NR8; R8 is nitro; R1 is heterocycle wherein heterocycle is selected from quinolinyl, pyridinyl and pyrimidinyl; R2 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkyl, alkylthioalkyl, aryl wherein aryl is phenyl, arylalkyl wherein the aryl portion of arylalkyl is phenyl, cyanoalkyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, (NR9R10)alkyl and heterocycle wherein heterocycle is selected from 1,3-dioxanyl, pyrrolidinyl and thienyl; R3 is aryl wherein aryl is phenyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R7, R9 and R10 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is NR8; R8 is selected from arylsulfonyl, haloalkylsulfonyl and sulfamyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R1, R2, R3, and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is NR8; R8 is selected from arylsulfonyl wherein the aryl portion of arylsulfonyl is phenyl, haloalkylsulfonyl and sulfamyl; R1 is heterocycle wherein heterocycle is selected from quinolinyl, pyridinyl and pyrimidinyl; R2 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkyl, alkylthioalkyl, aryl wherein aryl is phenyl, arylalkyl wherein the aryl portion of arylalkyl is phenyl, cyanoalkyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, (NR9R10)alkyl and heterocycle wherein heterocycle is selected from 1,3-dioxanyl, pyrrolidinyl and thienyl; R3 is aryl wherein aryl is phenyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R7, R9 and R10 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is S; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R1, R2, R3 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is S; R1 is selected from heterocycle and heterocyclealkyl; R3 is selected from aryl and arylalkyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R2 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is S; R1 is selected from heterocycle and heterocyclealkyl; R2 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkyl, alkylthioalkyl, aryl, arylalkyl, cyanoalkyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycle and (NR9R10)alkyl; R3 is selected from aryl and arylalkyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; and R9 and R10 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is S; R1 is heterocycle wherein heterocycle is selected from quinolinyl, pyridinyl and pyrimidinyl; R2 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkyl, alkylthioalkyl, aryl wherein aryl is phenyl, arylalkyl wherein the aryl portion of arylalkyl is phenyl, cyanoalkyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, (NR9R10)alkyl and heterocycle wherein heterocycle is selected from 1,3-dioxanyl, pyrrolidinyl and thienyl; R3 is aryl wherein aryl is phenyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; and R9 and R10 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is S; R1 is heterocycle; R2 is haloalkyl; R3 is aryl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula I wherein X is S; R1 is heterocycle wherein heterocycle is pyridinyl; R2 is haloalkyl; R3 is aryl wherein aryl is phenyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula I wherein X is S; R1 is selected from aryl and arylalkyl; R3 is selected from aryl and arylalkyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R2 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is S; R1 is selected from aryl and arylalkyl; R2 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkyl, alkylthioalkyl, aryl, arylalkyl, cyanoalkyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycle and (NR9R10)alkyl; R3 is selected from aryl and arylalkyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; and R9 and R10 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is S; R1 is aryl wherein aryl is phenyl; R2 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkyl, alkylthioalkyl, aryl wherein aryl is phenyl, arylalkyl wherein the aryl portion of arylalkyl is phenyl, cyanoalkyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, (NR9R10)alkyl and heterocycle wherein heterocycle is selected from 1,3-dioxanyl, pyrrolidinyl and thienyl; R3 is aryl wherein aryl is phenyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; and R9 and R10 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is S; R1 is aryl wherein aryl is phenyl; R2 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkyl, alkylthioalkyl, aryl wherein aryl is phenyl, arylalkyl wherein the aryl portion of arylalkyl is phenyl, cyanoalkyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, (NR9R10)alkyl and heterocycle wherein heterocycle is selected from 1,3-dioxanyl, pyrrolidinyl and thienyl; R3 is aryl wherein aryl is phenyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; and R9 and R10 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is O; R1 is selected from heterocycle and heterocyclealkyl; R3 is selected from aryl and arylalkyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R2 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is O; R1 is selected from heterocycle and heterocyclealkyl; R2 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkyl, alkylthioalkyl, aryl, arylalkyl, cyanoalkyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycle and (NR9R10)alkyl; R3 is selected from aryl and arylalkyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; and R9 and R10 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is O; R1 is heterocycle wherein heterocycle is selected from quinolinyl, pyridinyl and pyrimidinyl; R2 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkyl, alkylthioalkyl, aryl wherein aryl is phenyl, arylalkyl wherein the aryl portion of arylalkyl is phenyl, cyanoalkyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, (NR9R10)alkyl and heterocycle wherein heterocycle is selected from 1,3-dioxanyl, pyrrolidinyl and thienyl; R3 is aryl wherein aryl is phenyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; and R9 and R10 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is O; R1 is heterocycle; R2 is haloalkyl; R3 is aryl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula I wherein X is O; R1 is heterocycle wherein heterocycle is pyridinyl; R2 is haloalkyl; R3 is aryl wherein aryl is phenyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula I wherein X is O; R1 is selected from heterocycle and heterocyclealkyl; R3 is selected from heterocycle, and heterocyclealkyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R2 and R7 are as defined in forumula I.
In another embodiment of the present invention, compounds have formula I wherein X is O; R1 is selected from aryl and arylalkyl; R3 is selected from aryl and arylalkyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R2 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is O; R1 is selected from aryl and arylalkyl; R2 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkyl, alkylthioalkyl, aryl, arylalkyl, cyanoalkyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycle and (NR9R10)alkyl; R3 is selected from aryl and arylalkyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; and R9 and R10 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is O; R1 is aryl wherein aryl is phenyl; R2 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkyl, alkylthioalkyl, aryl wherein aryl is phenyl, arylalkyl wherein the aryl portion of arylalkyl is phenyl, cyanoalkyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, (NR9R10)alkyl and heterocycle wherein heterocycle is selected from 1,3-dioxanyl, pyrrolidinyl and thienyl; R3 is aryl wherein aryl is phenyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R7, R9 and R10 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is selected from CHCN and CHNO2; R1 is selected from heterocycle and heterocyclealkyl; R3 is selected from heterocycle and heterocyclealkyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R2 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is selected from CHCN and CHNO2; R1 is selected from heterocycle and heterocyclealkyl; R3 is selected from aryl and arylalkyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R2 and R7 are as defined in formual I.
In another embodiment of the present invention, compounds have formula I wherein X is selected from CHCN and CHNO2; R1 is selected from heterocycle and heterocyclealkyl; R2 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkyl, alkylthioalkyl, aryl, arylalkyl, cyanoalkyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocycle and (NR9R10)alkyl; R3 is selected from aryl and arylalkyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; and R9 and R10 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is selected from CHCN and CHNO2; R1 is heterocycle wherein heterocycle is selected from quinolinyl, pyridinyl and pyrimidinyl; R2 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkyl, alkylthioalkyl, aryl wherein aryl is phenyl, arylalkyl wherein the aryl portion of arylalkyl is phenyl, cyanoalkyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, (NR9R10)alkyl and heterocycle wherein heterocycle is selected from 1,3-dioxanyl, pyrrolidinyl and thienyl; R3 is aryl wherein aryl is phenyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; and R9 and R10 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is selected from CHCN and CHNO2; R1 is heterocycle wherein heterocycle is selected from quinolinyl, pyridinyl and pyrimidinyl; R2 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkyl, alkylthioalkyl, aryl wherein aryl is phenyl, arylalkyl wherein the aryl portion of arylalkyl is phenyl, cyanoalkyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, (NR9R10)alkyl and heterocycle wherein heterocycle is selected from 1,3-dioxanyl, pyrrolidinyl and thienyl; R3 is aryl wherein aryl is phenyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; and R9 and R10 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is selected from CHCN and CHNO2; R1 is heterocycle; R2 is haloalkyl; R3 is aryl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula I wherein X is selected from CHCN and CHNO2; R1 is heterocycle wherein heterocycle is pyridinyl; R2 is haloalkyl; R3 is aryl wherein aryl is phenyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula I wherein X is selected from CHCN and CHNO2; R1 is selected from heterocycle and heterocyclealkyl; R3 is alkyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R2 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is selected from CHCN and CHNO2; R1 is selected from aryl and arylalkyl; R3 is selected from heterocycle and heterocyclealkyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R2 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is selected from CHCN and CHNO2; R1 is selected from aryl and arylalkyl; R3 is selected from aryl and arylalkyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R2 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is selected from CHCN and CHNO2; R1 is selected from aryl and arylalkyl; R3 is alkyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R2 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is C(CN)2; R1 is selected from heterocycle and heterocyclealkyl; R3 is selected from aryl and arylalkyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R2 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula I wherein X is C(CN)2; R1 is heterocycle wherein heterocycle is selected from quinolinyl, pyridinyl and pyrimidinyl; R2 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkyl, alkylthioalkyl, aryl wherein aryl is phenyl, arylalkyl wherein the aryl portion of arylalkyl is phenyl, cyanoalkyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, (NR9R10)alkyl and heterocycle wherein heterocycle is selected from 1,3-dioxanyl, pyrrolidinyl and thienyl; R3 is aryl wherein aryl is phenyl; R4 is hydrogen; R5 is hydrogen; R6 is hydrogen; and R7, R9 and R10 are as defined in formula I.
In another embodiment of the present invention, compounds have formula II: 
or a pharmaceutically acceptable salt, amide, ester or prodrug thereof wherein Z and Y are independently selected from CH and N; A, B, and D are independently selected from hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfinyl, alkylsulfonyl, alkynyl, arylalkoxycarbonyl, arylsulfonyl, cyano, halo, haloalkyl, haloalkoxy, nitro, sulfamyl, and xe2x80x94NRARB; and X, R2, R3, R5, R6, R7, RA and RB are as defined in formula I.
In another embodiment of the present invention, compounds have formula II wherein X is NR8; R8 is cyano; R5 is hydrogen; R6 is hydrogen; A, B, D, Z and Y are as defined in formula II; and R2, R3 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula II wherein X is NR8; R8 is selected from hydrogen, alkoxy, alkyl, alkylsulfonyl, arylalkoxy, aryloxy, arylsulfonyl, haloalkylsulfonyl, heterocyclealkoxy, hydroxy, nitro, and sulfamyl; R5 is hydrogen; R6 is hydrogen; A, B, D, Z and Y are as defined in formula II; and R2, R3 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula II wherein X is S; R5 is hydrogen; R6 is hydrogen; A, B, D, Z and Y are as defined in formula II; and R2, R3 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula II wherein X is O; R5 is hydrogen; R6 is hydrogen; A, B, D, Z and Y are as defined in formula II; and R2, R3 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula II wherein X is selected from CHCN and CHNO2; R5 is hydrogen; R6 is hydrogen; A, B, D, Z and Y are as defined in formula II; and R2, R3 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula III: 
or a pharmaceutically acceptable salt, amide, ester or prodrug thereof wherein r is an integer of 1-2; E and G are independently selected from hydrogen, alkyl and oxo; and X, R1, R2, R3, R6 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula III wherein X is NR8; R8 is cyano; R6 is hydrogen; r, E and G are as defined in formula III; and R1, R2, R3 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula III wherein X is NR8; R8 is selected from hydrogen, alkoxy, alkyl, alkylsulfonyl, arylalkoxy, aryloxy, arylsulfonyl, haloalkylsulfonyl, heterocyclealkoxy, hydroxy, nitro, and sulfamyl; R6 is hydrogen; r, E and G are as defined in formula III; and R1, R2, R3 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula III wherein X is S; R6 is hydrogen; r, E and G are as defined in formula III; and R1, R2, R3 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula III wherein R2 is haloalkyl; R7 is hydrogen; r, E and G are as defined in formula III; and X, R1, R3 and R6 are as defined in formula I.
In another embodiment of the present invention, compounds have formula III wherein X is O; R6 is hydrogen; r, E and G are as defined in formula III; and R1, R2, R3 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula III wherein X is selected from CHCN and CHNO2; R6 is hydrogen; r, E and G are as defined in formula III; and R1, R2, R3 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula IV: 
or a pharmaceutically acceptable salt, amide, ester or prodrug thereof wherein t is an integer of 1-2; J and K are independently selected from hydrogen, alkyl and oxo; and X, R1, R2, R3, R4 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula IV wherein X is NR8; R8 is cyano; R4 is hydrogen; t, J and K are as defined in formula IV; and R1, R2, R3 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula IV wherein X is NR8; R8 is selected from hydrogen, alkoxy, alkyl, alkylsulfonyl, arylalkoxy, aryloxy, arylsulfonyl, haloalkylsulfonyl, heterocyclealkoxy, hydroxy, nitro, and sulfamyl; R4 is hydrogen; t, J and K are as defined in formula IV; and R1, R2, R3 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula IV wherein X is S; R4 is hydrogen; t, J and K are as defined in formula IV; and R1, R2, R3 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula IV wherein X is O; R4 is hydrogen; t, J and K are as defined in formula IV; and R1, R2, R3 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula IV wherein X is selected from CHCN and CHNO2; R4 is hydrogen; t, J and K are as defined in formula IV; and R1, R2, R3 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula V: 
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof wherein p is an integer of 1-2; L, M and Q are independently selected from hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfinyl, alkylsulfonyl, alkynyl, arylalkoxycarbonyl, arylsulfonyl, cyano, halo, haloalkyl, haloalkoxy, nitro, sulfamyl, and xe2x80x94NRARB; and X, R1, R2, R4, R5, R7, RA and RB are as defined in formula I.
In another embodiment of the present invention, compounds have formula V wherein X is NR8; R8 is cyano; R4 is hydrogen; R5 is hydrogen; p, L, M and Q are as defined in formula V; and R1, R2 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula V wherein X is NR8; R8 is selected from hydrogen, alkoxy, alkyl, alkylsulfonyl, arylalkoxy, aryloxy, arylsulfonyl, haloalkylsulfonyl, heterocyclealkoxy, hydroxy, nitro, and sulfamyl; R4 is hydrogen; R5 is hydrogen; p, L, M and Q are as defined in formula V; and R1, R2 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula V wherein X is S; R4 is hydrogen; R5 is hydrogen; p, L, M and Q are as defined in formula V; and R1, R2 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula V wherein X is O; R4 is hydrogen; R5 is hydrogen; p, L, M and Q are as defined in formula V; and R1, R2 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula V wherein X is selected from CHCN and CHNO2; R4 is hydrogen; R5 is hydrogen; p, L, M and Q are as defined in formula V; and R1, R2 and R7 are as defined in formula I.
In another embodiment of the present invention, compounds have formula VI: 
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof wherein X, R1, R2, R3, R4, R6, R7 and R12 are as defined in formula I.
In another embodiment of the present invention, compounds have formula VI wherein X is NR8; R8 is cyano; R4 is hydrogen; R6 is hydrogen; R1, R2, R3, R7 and R12 are as defined in formula I.
In another embodiment of the present invention, compounds have formula VI wherein X is NR8; R8 is selected from hydrogen, alkoxy, alkyl, alkylsulfonyl, arylalkoxy, aryloxy, arylsulfonyl, haloalkylsulfonyl, heterocyclealkoxy, hydroxy, nitro, and sulfamyl; R4 is hydrogen; R6 is hydrogen; and R1, R2, R3, R7 and R12 are as defined in formula I.
In another embodiment of the present invention, compounds have formula VI wherein X is S; R4 is hydrogen; R6 is hydrogen; and R1, R2, R3, R7 and R12 are as defined in formula I.
In another embodiment of the present invention, compounds have formula VI wherein X is O; R4 is hydrogen; R6 is hydrogen; and R1, R2, R3, R7 and R12 are as defined in formula I.
In another embodiment of the present invention, compounds have formula VI wherein X is S; X is selected from CHCN and CHNO2; R4 is hydrogen; R6 is hydrogen; and R1, R2, R3, R7 and R12 are as defined in formula I.
Another embodiment of the invention relates to a method of treating a disease in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula VII: 
or a pharmaceutically acceptable salt, amide, ester or prodrug thereof wherein R1 is phenyl; and R3 is selected from alkyl and phenyl.
Another embodiment of the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I-VII or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof in combination with a pharmaceutically acceptable carrier.
Another embodiment of the invention relates to a method of treating urinary incontinence comprising administering a therapeutically effective amount of a compound of formula I-VII or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
Another embodiment of the invention relates to a method of treating male sexual dysfunction including, but not limited to, male erectile dysfunction and premature ejaculation, comprising administering a therapeutically effective amount of a compound of formula I-VII or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
Another embodiment of the invention relates to a method of treating female sexual dysfunction including, but not limited to, female anorgasmia, clitoral erectile insufficiency, vaginal engorgement, dyspareunia, and vaginismus comprising administering a therapeutically effective amount of a compound of formula I-VII or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
Yet another embodiment of the invention relates to a method of treating asthma, epilepsy, Raynaud""s syndrome, intermittent claudication, migraine, pain, bladder overactivity, pollakiuria, bladder instability, nocturia, bladder hyperreflexia, eating disorders, urinary incontinence, enuresis, functional bowel disorders, neurodegeneration, benign prostatic hyperplasia (BPH), dysmenorrhea, premature labor, alopecia, cardioprotection, and ischemia comprising administering a therapeutically effective amount of a compound of formula I-VII or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
As used throughout this specification and the appended claims, the following terms have the following meanings.
The term xe2x80x9calkenyl,xe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbonxe2x80x94carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 1,1-dimethyl-3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, 3-decenyl and the like.
The term xe2x80x9calkenyloxy,xe2x80x9d as used herein, refers to an alkenyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of alkenyloxy include, but are not limited to, allyloxy, 2-butenyloxy, 3-butenyloxy and the like.
The term xe2x80x9calkenyloxyalkyl,xe2x80x9d as used herein, refers to a alkenyloxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkenyloxyalkyl include, but are not limited to, (allyloxy)methyl, (2-butenyloxy)methyl and (3-butenyloxy)methyl.
The term xe2x80x9calkenyloxy(alkenyloxy)alkyl,xe2x80x9d as used herein, refers to 2 independent alkenyloxy groups, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkenyloxy(alkenyloxy)alkyl include, but are not limited to, 1,2-bis(allyloxy)ethyl and 1,1-bis[(allyloxy)methyl]propyl and the like.
The term xe2x80x9calkoxy,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, and the like.
The term xe2x80x9calkoxyalkyl,xe2x80x9d as used herein, refers to an alkoxy group, as defied herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, methoxymethyl, 1,1-dimethyl-3-(methoxy)propyl, and the like.
The term xe2x80x9calkoxycarbonyl,xe2x80x9d as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, and the like.
The term xe2x80x9calkoxycarbonylalkyl,xe2x80x9d as used herein, refers to an alkoxycarbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxycarbonylalkyl include, but are not limited to, methoxycarbonylmethyl, ethoxycarbonylmethyl, tert-butoxycarbonylmethyl, 1,1-dimethyl-2-(methoxycarbonyl)ethyl and the like.
The term xe2x80x9calkoxycarbonyl(halo)alkyl,xe2x80x9d as used herein, refers to an alkoxycarbonyl group and at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxycarbonyl(halo)alkyl include, but are not limited to, 1,1-dichloro-2-methoxy-2-oxoethyl, 1,1-difluoro-2-methoxy-2-oxoethyl, 1,1-dichloro-3-methoxy-3-oxopropyl, 1,1-difluoro-3-methoxy-3-oxopropyl, and the like.
The term xe2x80x9calkoxy(halo)alkyl,xe2x80x9d as used herein, refers to an alkoxy group and at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxy(halo)alkyl include, but are not limited to, dichloro(methoxy)methyl, dichloro(ethoxy)methyl, dichloro(tert-butoxy)methyl, 1,1-dichloro-2-ethoxyethyl, 1,1-dichloro-2-methoxyethyl, 1,1-dichloro-3-methoxypropyl, 1,2-dichloro-3-methoxypropyl, and the like.
The term xe2x80x9calkyl,xe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 1-ethylpropyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.
The term xe2x80x9calkylcarbonyl,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, 1-oxopentyl, and the like.
The term xe2x80x9calkylcarbonylalkyl,xe2x80x9d as used herein, refers to an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkylcarbonylalkyl include, but are not limited to, 2-oxopropyl, 1,1-dimethyl-3-oxobutyl, 3-oxobutyl, 3-oxopentyl, and the like.
The term xe2x80x9calkylcarbonyl(halo)alkyl,xe2x80x9d as used herein, refers to an alkylcarbonyl group and at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkylcarbonyl(halo)alkyl include, but are not limited to, 1,1-dichloro-2-oxopropyl, 1,1-dichloro-3-oxobutyl, 1,1-difluoro-3-oxobutyl, 1,1-dichloro-3-oxopentyl, and the like.
The term xe2x80x9calkylcarbonyloxy,xe2x80x9d as used herein, refers to an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and the like.
The term xe2x80x9calkylcarbonyloxyalkyl,xe2x80x9d as used herein, refers to an alkylcarbonyloxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkylcarbonyloxyalkyl include, but are not limited to, acetyloxymethyl, 2-(ethylcarbonyloxy)ethyl, and the like.
The term xe2x80x9calkylenexe2x80x9d or xe2x80x9calkylene bridgexe2x80x9d refers to a divalent group derived from a straight chain hydrocarbon of from 2 to 6 carbon atoms. The alkylene or alkylene bridge can be optionally substituted with 1 or 2 substituents selected from alkyl and oxo. Representative examples of alkylene or alkylene bridge include, but are not limited to, xe2x80x94CH2CH2xe2x80x94, xe2x80x94C(O)CH2xe2x80x94, xe2x80x94C(O)C(O)xe2x80x94, xe2x80x94CH2CH2CH2xe2x80x94, xe2x80x94CH2C(CH3)2CH2xe2x80x94, xe2x80x94CH2CH2CH2CH2xe2x80x94, xe2x80x94CH2CH2CH2CH2CH2xe2x80x94 and the like.
The term xe2x80x9calkylsulfinyl,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfinyl group, as defined herein. Representative examples of alkylsulfinyl include, but are not limited to, methylsulfinyl, ethylsulfinyl, and the like.
The term xe2x80x9calkylsulfinylalkyl,xe2x80x9d as used herein, refers to an alkylsulfinyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkylsulfinylalkyl include, but are not limited to, methylsulfinylmethyl, ethylsulfinylmethyl, and the like.
The term xe2x80x9calkylsulfonyl,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of alkylsulfonyl include, but are not limited to, methylsulfonyl, ethylsulfonyl, and the like.
The term xe2x80x9calkylsulfonylalkyl,xe2x80x9d as used herein, refers to an alkylsulfonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkylsulfonylalkyl include, but are not limited to, methylsulfonylmethyl, ethylsulfonylmethyl, and the like.
The term xe2x80x9calkylthio,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein. Representative examples of alkylthio include, but are not limited to, methylsulfanyl, ethylsulfanyl, propylsulfanyl, 2-propylsulfanyl, tert-butylsulfanyl, and the like.
The term xe2x80x9calkylthioalkyl,xe2x80x9d as used herein, refers to an alkylthio group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkylthioalkyl include, but are not limited to, tert-butylsulfanylmethyl, 2-ethylsulfanylethyl, 2-methylsulfanylethyl, methylsulfanylmethyl, and the like.
The term xe2x80x9calkynyl,xe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbonxe2x80x94carbon triple bond. Representative examples of alkynyl include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, 1-butynyl, and the like.
The term xe2x80x9camido,xe2x80x9d as used herein, refers to a xe2x80x94NR9R10 group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of amido include, but are not limited to, aminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, benzylaminocarbonyl, and the like.
The term xe2x80x9camidoalkyl,xe2x80x9d as used herein, refers to an amido group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of amidoalkyl include, but are not limited to, aminocarbonylmethyl, dimethylaminocarbonylmethyl, 2-(ethylaminocarbonyl)ethyl, 3-(benzylaminocarbonyl)propyl, and the like.
The term xe2x80x9caryl,xe2x80x9d as used herein, refers to a monocyclic carbocyclic ring system or a bicyclic carbocyclic fused ring system having one or more aromatic rings. Representative examples of aryl include, azulenyl, indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl, and the like.
The aryl groups of this invention, including the representative examples listed above, can be optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkylsulfinyl, alkylsulfonyl, alkynyl, amido, amidoalkyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylcarbonyloxy, arylcarbonyloxyalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, arylsulfonyl, cyano, halo, haloalkyl, haloalkoxy, nitro, sulfamyl, sulfamylalkyl, xe2x80x94NRARB, (NRARB)alkyl, furyl, imidazolyl, isothiazolyl, isoxazolyl, naphthyl, oxadiazolyl, oxazolyl, phenyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzothienyl, benzoxadiazolyl, benzoxazolyl, benzofuranyl, cinnolinyl, indolyl, naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, and quinolinyl, wherein said furyl, imidazolyl, isothiazolyl, isoxazolyl, naphthyl, oxadiazolyl, oxazolyl, phenyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzothienyl, benzoxadiazolyl, benzoxazolyl, benzofuranyl, cinnolinyl, indolyl, naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, and quinolinyl may be substituted with 1 or 2 substituents independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkylsulfinyl, alkylsulfonyl, alkynyl, amido, amidoalkyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylcarbonyloxy, arylcarbonyloxyalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, arylsulfonyl, cyano, halo, haloalkyl, haloalkoxy, nitro, sulfamyl, sulfamylalkyl, xe2x80x94NRARB, and (NRARB)alkyl.
The term xe2x80x9carylalkoxy,xe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of arylalkoxy include, but are not limited to, 2-phenylethoxy, 3-naphth-2-ylpropoxy, 5-phenylpentyloxy, and the like.
The term xe2x80x9carylalkoxyalkyl,xe2x80x9d as used herein, refers to an arylalkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkoxyalkyl include, but are not limited to, 2-phenylethoxymethyl, 2-(3-naphth-2-ylpropoxy)ethyl, 5-phenylpentyloxymethyl, and the like.
The term xe2x80x9carylalkoxycarbonyl,xe2x80x9d as used herein, refers to an arylalkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylalkoxycarbonyl include, but are not limited to, benzyloxycarbonyl, naphth2-ylmethyloxycarbonyl, and the like.
The term xe2x80x9carylalkoxycarbonylalkyl,xe2x80x9d as used herein, refers to an arylalkoxycarbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkoxycarbonylalkyl include, but are not limited to, benzyloxycarbonylmethyl, 2-(benzyloxycarbonyl)ethyl, 2-(naphth-2-ylmethyloxycarbonyl)ethyl, and the like.
The term xe2x80x9carylalkyl,xe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 1,1-dimethyl-2-phenylethyl, 3-phenylpropyl, 2-naphth-2-ylethyl, and the like.
The term xe2x80x9carylalkylthio,xe2x80x9d as used herein, refers to an arylalkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein. Representative examples of arylalkylthio include, but are not limited to, 2-phenylethylthio, 3-naphth-2-ylpropylthio, 5-phenylpentylthio, and the like.
The term xe2x80x9carylalkylthioalkyl,xe2x80x9d as used herein, refers to an arylalkylthio group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkylthioalkyl include, but are not limited to, 2-phenylethylsulfanylmethyl, 3-naphth-2-ylpropylsulfanylmethyl, 2-(5-phenylpentylsulfanyl)ethyl, and the like.
The term xe2x80x9carylcarbonyl,xe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylcarbonyl include, but are not limited to, benzoyl, naphthoyl, and the like.
The term xe2x80x9carylcarbonylalkyl,xe2x80x9d as used herein, refers to an arylcarbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylcarbonylalkyl include, but are not limited to, 2-oxo-3-phenylpropyl, 1,1-dimethyl-3-oxo-4-phenylbutyl, and the like.
The term xe2x80x9carylcarbonyloxy,xe2x80x9d as used herein, refers to an arylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of arylcarbonyloxy include, but are not limited to, benzoyloxy, naphthoyloxy, and the like.
The term xe2x80x9carylcarbonyloxyalkyl,xe2x80x9d as used herein, refers to an arylcarbonyloxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylcarbonyloxyalkyl include, but are not limited to, benzoyloxymethyl, 2-(benzoyloxy)ethyl, 2-(naphthoyloxy)ethyl, and the like.
The term xe2x80x9caryl(halo)alkyl,xe2x80x9d as used herein, refers to an aryl group and at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of aryl(halo)alkyl include, but are not limited to, dichloro(phenyl)methyl, 1,1-dichloro-2-phenylethyl, 1,1-difluoro-2-phenylethyl, 1,1-dichloro-3-phenylpropyl, 1,1-difluoro-3-phenylpropyl, and the like.
The term xe2x80x9caryloxy,xe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of aryloxy include, but are not limited to, phenoxy, naphthyloxy, 3-bromophenoxy, 4-chlorophenoxy, 4-methylphenoxy, 3,5-dimethoxyphenoxy, and the like.
The term xe2x80x9caryloxyalkyl,xe2x80x9d as used herein, refers to an aryloxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of aryloxyalkyl include, but are not limited to, 2-phenoxyethyl, 3-naphth-2-yloxypropyl, 3-bromophenoxymethyl, and the like.
The term xe2x80x9caryloxycarbonyl,xe2x80x9d as used herein, refers to an aryloxy group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of aryloxycarbonyl include, but are not limited to, phenoxycarbonyl, naphthyloxycarbonyl, and the like.
The term xe2x80x9caryloxycarbonylalkyl,xe2x80x9d as used herein, refers to an aryloxycarbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of aryloxycarbonylalkyl include, but are not limited to, phenoxycarbonylmethyl, 2-(phenoxycarbonyl)ethyl, naphthyloxycarbonyl, and the like.
The term xe2x80x9carylsulfonyl,xe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of arylsulfonyl include, but are not limited to, naphthylsulfonyl, phenylsulfonyl, 4-fluorophenylsulfonyl, and the like.
The term xe2x80x9carylsulfonylalkyl,xe2x80x9d as used herein, refers to an arylsulfonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylsulfonylalkyl include, but are not limited to, 1,1-dimethyl-3-(phenylsulfonyl)propyl, naphthylsulfonylmethyl, 2-(phenylsulfonyl)ethyl, phenylsulfonylmethyl, 4-fluorophenylsulfonylmethyl, and the like.
The term xe2x80x9carylthio,xe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein. Representative examples of arylthio include, but are not limited to, phenylsulfanyl, naphth-2-ylsulfanyl, 5-phenylhexylsulfanyl, and the like.
The term xe2x80x9carylthioalkyl,xe2x80x9d as used herein, refers to an arylthio group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylthioalkyl include, but are not limited to, phenylsulfanylmethyl, 2-naphth-2-ylsulfanylethyl, 5-phenylhexylsulfanylmethyl, and the like.
The term xe2x80x9ccarbonyl,xe2x80x9d as used herein, refers to axe2x80x94C(O)xe2x80x94 group.
The term xe2x80x9ccarboxy,xe2x80x9d as used herein, refers to a xe2x80x94CO2H group.
The term xe2x80x9ccarboxyalkyl,xe2x80x9d as used herein, refers to a carboxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 3-carboxy-1,1-dimethylpropyl and the like.
The term xe2x80x9ccarboxy(halo)alkyl,xe2x80x9d as used herein, refers to a carboxy group and at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of carboxy(halo)alkyl include, but are not limited to, carboxy(dichloro)methyl, carboxy(difluoro)methyl, 2-carboxy 1,1-dichloroethyl, 2-carboxy-1,1-difluoroethyl, and the like.
The term xe2x80x9ccyano,xe2x80x9d as used herein, refers to a xe2x80x94CN group.
The term xe2x80x9ccyanoalkyl,xe2x80x9d as used herein, refers to a cyano group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, 3-cyano-1,1-dimethylpropyl, 3-cyano-1,1-diethylpropyl and the like.
The term xe2x80x9ccyano(halo)alkyl,xe2x80x9d as used herein, refers to a cyano group and at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cyano(halo)alkyl include, but are not limited to, 3-cyano-1,1-difluoropropyl, 1,1-dichloro-3-cyanopropyl, 3-cyano-1,1-bis(trifluoromethyl)propyl, and the like.
The term xe2x80x9ccycloalkenyl,xe2x80x9d as used herein, refers to a cyclic hydrocarbon containing from 3 to 8 carbons and containing at least one carbonxe2x80x94carbon double bond formed by the removal of two hydrogens. Representative examples of cycloalkenyl include, but are not limited to, cyclohexene, 1-cyclohexen-2-yl, 3,3-dimethyl-1-cyclohexene, cyclopentene, cycloheptene, and the like.
The cycloalkenyl groups of this invention can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkynyl, amido, amidoalkyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylcarbonyloxy, arylcarbonyloxyalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, sulfamylalkyl, xe2x80x94NRARB, (NRARB)alkyl.
The term xe2x80x9ccycloalkenylalkyl,xe2x80x9d as used herein, refers to a cycloalkenyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cycloalkenylalkyl include, but are not limited to, (2,6,6-trimethyl-1-cyclohexen-1-yl)methyl, 1-cyclohexen-1-ylmethyl, 2-(2-cyclohepten-1-yl)ethyl, and the like.
The term xe2x80x9ccycloalkyl,xe2x80x9d as used herein, refers to a monocyclic, bicyclic, or tricyclic ring system. Monocyclic ring systems are exemplified by a saturated cyclic hydrocarbon group containing from 3 to 8 carbon atoms. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Bicyclic ring systems are exemplified by a bridged monocyclic ring system in which two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms. Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo [2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo [3.3.1 ]nonane, and bicyclo[4.2.1]nonane. Tricyclic ring systems are exemplified by a bicyclic ring system in which two non-adjacent carbon atoms of the bicyclic ring are linked by a bond or an alkylene bridge of between one and three carbon atoms. Representative examples of tricyclic-ring systems include, but are not limited to, tricyclo[3.3.1.03,7]nonane and tricyclo[3.3.1.13,7]decane (adamantane).
The cycloalkyl groups of this invention can be optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkylsulfonylalkyl, alkynyl, alkylcarbonyloxy, amido, amidoalkyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylalkyl, arylcarbonyloxy, arylcarbonyloxyalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, arylsulfonylalkyl, cyanoalkyl, cycloalkylalkyl, halo, haloalkoxy, haloalkyl, heterocyclealkyl, hydroxy, hydroxyalkyl, sulfamylalkyl, xe2x80x94NRARB, and (NRARB)alkyl.
The term xe2x80x9ccycloalkylalkoxy,xe2x80x9d as used herein, refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of cycloalkylalkoxy include, but are not limited to, cyclopropylmethoxy, 2-cyclobutylethoxy, cyclopentylmethoxy, cyclohexylmethoxy, 4-cycloheptylbutoxy, and the like.
The term xe2x80x9ccycloalkylalkoxyalkyl,xe2x80x9d as used herein, refers to a cycloalkylalkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cycloalkylalkoxyalkyl include, but are not limited to, cyclopropylmethoxymethyl, 2-cyclobutylethoxymethyl, cyclopentylmethoxymethyl, 2-cyclohexylethoxymethyl, 2-(4-cycloheptylbutoxy)ethyl, and the like.
The term xe2x80x9ccycloalkylalkyl,xe2x80x9d as used herein, refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl and 4-cycloheptylbutyl, and the like.
The term xe2x80x9ccycloalkylcarbonyl,xe2x80x9d as used herein, refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of cycloalkylcarbonyl include, but are not limited to, cyclopropylcarbonyl, 2-cyclobutylcarbonyl, cyclohexylcarbonyl, and the like.
The term xe2x80x9ccycloalkyloxy,xe2x80x9d as used herein, refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of cycloalkyloxy include, but are not limited to, cyclohexyloxy, cyclopentyloxy, and the like.
The term xe2x80x9ccycloalkyloxyalkyl,xe2x80x9d as used herein, refers to a cycloalkyloxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cycloalkyloxyalkyl include, but are not limited to, 4-(cyclohexyloxy)butyl, cyclohexyloxymethyl, and the like.
The term xe2x80x9ccycloalkylalkylthio,xe2x80x9d as used herein, refers to a cycloalkylalkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein. Representative examples of cycloalkylalkylthio include, but are not limited to, (2-cyclohexylethyl)sulfanyl, cyclohexylmethylsulfanyl, and the like.
The term xe2x80x9ccycloalkylalkylthioalkyl,xe2x80x9d as used herein, refers to a cycloalkylalkylthio group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cycloalkylalkylthioalkyl include, but are not limited to, 2-[(2-cyclohexylethyl)sulfanyl]ethyl, (2-cyclohexylethyl)sulfanylmethyl, and the like.
The term xe2x80x9ccycloalkylthio,xe2x80x9d as used herein, refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein. Representative examples of cycloalkylthio include, but are not limited to, cyclohexylsulfanyl, cyclopentylsulfanyl, and the like.
The term xe2x80x9ccycloalkylthioalkyl,xe2x80x9d as used herein, refers to a cycloalkylthio group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cycloalkylthioalkyl include, but are not limited to, 4-(cyclohexylsulfanyl)butyl, cyclohexylsulfanylmethyl, and the like.
The term xe2x80x9cformyl,xe2x80x9d as used herein, refers to a xe2x80x94C(O)H group.
The term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogen,xe2x80x9d as used herein, refers to xe2x80x94Cl, xe2x80x94Br, xe2x80x94I or xe2x80x94F.
The term xe2x80x9chaloalkoxy,xe2x80x9d as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, 1,2-difluoroethoxy, trifluoromethoxy, pentafluoroethoxy, and the like.
The term xe2x80x9chaloalkenyl,xe2x80x9d as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkenyl group, as defined herein. Representative examples of haloalkenyl include, but are not limited to, 2,2-dichloroethenyl, 2,2-difluoroethenyl, 5-chloropenten-2-yl, and the like.
The term xe2x80x9chaloalkyl,xe2x80x9d as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, trichloromethyl, 1,1-dichloroethyl, 2-fluoroethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trifluoro-1-(trifluoromethyl)-1-(methyl)ethyl, pentafluoroethyl, 2-chloro-3-fluoropentyl, and the like.
The term xe2x80x9chaloalkylcarbonyl,xe2x80x9d as used herein, refers to a haloalkylgroup, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of haloalkylcarbonyl include, but are not limited to, chloromethylcarbonyl, trichloromethylcarbonyl, trifluoromethylcarbonyl, and the like.
The term xe2x80x9chaloalkylsulfonyl,xe2x80x9d as used herein, refers to a haloalkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of haloalkylsulfonyl include, but are not limited to, chloromethylsulfonyl, trichloromethylsulfonyl, trifluoromethylsulfonyl, and the like.
The term xe2x80x9chaloalkynyl,xe2x80x9d as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkynyl group, as defined herein. Representative examples of haloalkynyl include, but are not limited to, 4,4,4-trichlorobutyn-2-yl, and the like.
The term xe2x80x9cheterocycle,xe2x80x9d as used herein, refers to a monocyclic or a bicyclic ring system. Monocyclic ring systems are exemplified by any 5 or 6 membered ring containing 1, 2, 3, or 4 heteroatoms independently selected from oxygen, nitrogen and sulfur. The 5-membered ring has from 0-2 double bonds and the 6-membered ring has from 0-3 double bonds. Representative examples of monocyclic ring systems include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxolanyl, dioxanyl, 1,3-dioxanyl, dithianyl, furyl, imidazolyl, imidazolinyl, imidazolidinyl, isothiazolyl, isothiazolinyl, isothiazolidinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolyl, oxadiazolinyl, oxadiazolidinyl, oxazolyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiadiazolinyl, thiadiazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, thienyl, thiomorpholinyl, thiomorpholine sulfone, thiopyranyl, triazinyl, triazolyl, trithianyl, and the like. Bicyclic ring systems are exemplified by any of the above monocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or another monocyclic ring system as defined herein. Representative examples of bicyclic ring systems include but are not limited to, for example, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzothienyl, benzoxadiazolyl, benzoxazolyl, benzofuranyl, benzopyranyl, benzothiopyranyl, benzotriazolyl, benzodioxinyl, 1,3-benzodioxolyl, cinnolinyl, indazolyl, indolyl, indolinyl, indolizinyl, naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoindolinyl, 1-isoindolinonyl, isoquinolinyl, 1-isoquinolinonyl, phthalazinyl, pyranopyridinyl, quinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, and thiopyranopyridinyl.
The heterocycle groups of this invention, including the representative examples listed above, can be optionally substituted with 1, 2, or 3 substituents independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkylsulfinyl, alkylsulfonyl, alkynyl, amido, amidoalkyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylcarbonyloxy, arylcarbonyloxyalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, arylsulfonyl, cyano, halo, haloalkyl, haloalkoxy, nitro, oxo, sulfamyl, sulfamylalkyl, xe2x80x94NRARB, (NRARB)alkyl, furyl, imidazolyl, isothiazolyl, isoxazolyl, naphthyl, oxadiazolyl, oxazolyl, phenyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzothienyl, benzoxadiazolyl, benzoxazolyl, benzofuranyl, cinnolinyl, indolyl, naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, and quinolinyl wherein said furyl, imidazolyl, isothiazolyl, isoxazolyl, naphthyl, oxadiazolyl, oxazolyl, phenyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzothienyl, benzoxadiazolyl, benzoxazolyl, benzofuranyl, cinnolinyl, indolyl, naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, and quinolinyl may be substituted with 1 or 2 substituents independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkylsulfinyl, alkylsulfonyl, alkynyl, amido, amidoalkyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylcarbonyloxy, arylcarbonyloxyalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, arylsulfonyl, cyano, halo, haloalkyl, haloalkoxy, nitro, sulfamyl, sulfamylalkyl, xe2x80x94NRARB, and (NRARB)alkyl.
The term xe2x80x9cheterocyclealkoxy,xe2x80x9d as used herein, refers to a heterocycle group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of heterocyclealkoxy include, but are not limited to, 2-pyrid-3-ylethoxy, 3-quinolin-3-ylpropoxy, 5-pyrid-4-ylpentyloxy, and the like.
The term xe2x80x9cheterocyclealkoxyalkyl,xe2x80x9d as used herein, refers to a heterocyclealkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heterocyclealkoxyalkyl include, but are not limited to, 2-pyrid-3-ylethoxymethyl, 2-(3-quinolin-3-ylpropoxy)ethyl, 5-pyrid-4-ylpentyloxymethyl, and the like.
The term xe2x80x9cheterocyclealkyl,xe2x80x9d as used herein, refers to a heterocycle, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heterocyclealkyl include, but are not limited to, pyrid-3-ylmethyl, pyrimidin-5-ylmethyl, and the like.
The term xe2x80x9cheterocyclealkylthio,xe2x80x9d as used herein, refers to a heterocyclealkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein. Representative examples of heterocyclealkylthio include, but are not limited to, 2-pyrid-3-ylethysulfanyl, 3-quinolin-3-ylpropysulfanyl, 5-pyrid-4-ylpentylsulfanyl, and the like.
The term xe2x80x9cheterocyclealkylthioalkyl,xe2x80x9d as used herein, refers to a heterocyclealkylthio group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heterocyclealkylthioalkyl include, but are not limited to, 2-pyrid-3-ylethysulfanylmethyl, 2-(3-quinolin-3-ylpropysulfanyl)ethyl, 5-pyrid-4-ylpentylsulfanylmethyl, and the like.
The term xe2x80x9cheterocyclecarbonyl,xe2x80x9d as used herein, refers to a heterocycle, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of heterocyclecarbonyl include, but are not limited to, pyrid-3-ylcarbonyl, quinolin-3-ylcarbonyl, thiophen-2-ylcarbonyl, and the like.
The term xe2x80x9cheterocycleoxy,xe2x80x9d as used herein, refers to a heterocycle group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of heterocycleoxy include, but are not limited to, pyrid-3-yloxy, quinolin-3-yloxy, and the like.
The term xe2x80x9cheterocycleoxyalkyl,xe2x80x9d as used herein, refers to a heterocycleoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heterocycleoxyalkyl include, but are not limited to, pyrid-3-yloxymethyl, 2-quinolin-3-yloxyethyl, and the like.
The term xe2x80x9cheterocyclethio,xe2x80x9d as used herein, refers to a heterocycle group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein. Representative examples of heterocyclethio include, but are not limited to, pyrid-3-ylsulfanyl, quinolin-3-ylsulfanyl, and the like.
The term xe2x80x9cheterocyclethioalkyl,xe2x80x9d as used herein, refers to a heterocyclethio group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heterocyclethioalkyl include, but are not limited to, pyrid-3-ylsulfanylmethyl, 2-quinolin-3-ylsulfanylethyl, and the like.
The term xe2x80x9chydroxy,xe2x80x9d as used herein, refers to an xe2x80x94OH group.
The term xe2x80x9chydroxyalkyl,xe2x80x9d as used herein, refers to 1 or 2 hydroxy groups, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 2-ethyl-4-hydroxyheptyl, 2-hydroxy-1,1-dimethylethyl, 3-hydroxy-1,1-dimethylpropyl, and the like.
The term xe2x80x9cLewis acid,xe2x80x9d as used herein, refers to a chemical species that has a vacant orbital or can accept an electron pair. Representative examples of Lewis acid include, but are not limited to, aluminum chloride, boron trifluoride, iron(II) chloride, iron(III) chloride, magnesium bromide, magnesium chloride, magnesium trifluoromethanesulfonate, manganese(II) chloride, titanium(IV) isopropoxide, zinc bromide, zinc chloride, zirconium(IV) chloride, and the like.
The term xe2x80x9clower alkyl,xe2x80x9d as used herein, is a subset of alkyl as defined herein and refers to a straight or branched chain hydrocarbon group containing from 1 to 6 carbon atoms. Representative examples of lower alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, and the like.
The term xe2x80x9cmercapto,xe2x80x9d as used herein, refers to a xe2x80x94SH group.
The term xe2x80x9cmercaptoalkyl,xe2x80x9d as used herein, refers to a mercapto group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of mercaptoalkyl include, but are not limited to, 2-sulfanylethyl, 3-sulfanylpropyl, and the like.
The term xe2x80x9cxe2x80x94NR9R10,xe2x80x9d as used herein, refers to two groups, R9 and R10, which are appended to the parent molecular moiety through a nitrogen atom. R9 and R10 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl, formyl, and S(O)2R11, as defined herein, wherein R11 is selected from alkyl, aryl, and arylalkyl, as defined herein. Representative examples of xe2x80x94NR9R10 include, but are not limited to, acetylamino, amino, methylamino, (ethylcarbonyl)methylamino, ethylmethylamino, formylamino, methylsulfonylamino, phenylsulfonylamino, benzylsulfonylamino, and the like.
The term xe2x80x9c(NR9R10)alkyl,xe2x80x9d as used herein, refers to a xe2x80x94NR9R10 group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of (NR9R10)alkyl include, but are not limited to, acetylaminomethyl, aminomethyl, 2-aminoethyl, 2-(methylamino)ethyl, (ethylcarbonyl)methylaminomethyl, 3-(ethylmethylamino)propyl, 1,1-dimethyl-3-(dimethylamino)propyl, 2-(formylamino)ethyl, methylsulfonylaminomethyl, 2-(phenylsulfonylamino)ethyl, benzylsulfonylaminomethyl, and the like.
The term xe2x80x9cxe2x80x94NRARB,xe2x80x9d as used herein, refers to two groups, RA and RB, which are appended to the parent molecular moiety through a nitrogen atom. RA and RB are independently selected from hydrogen, alkyl, alkylcarbonyl and formyl, as defined herein. Representative examples of xe2x80x94NRARB include, but are not limited to, acetylamino, amino, methylamino, (ethylcarbonyl)methylamino, dimethylamino, ethylmethylamino, formylamino, and the like.
The term xe2x80x9c(NRARB)alkyl,xe2x80x9d as used herein, refers to a xe2x80x94NRARB group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of (NRARB)alkyl include, but are not limited to, acetylaminomethyl, aminomethyl, 2-aminoethyl, 2-(methylamino)ethyl, (ethylcarbonyl)methylaminomethyl, 3-(ethylmethylamino)propyl, 1,1-dimethyl-3-(dimethylamino)propyl, 2-(formylamino)ethyl, and the like.
The term xe2x80x9cnitro,xe2x80x9d as used herein, refers to a xe2x80x94NO2 group.
The term xe2x80x9coxo,xe2x80x9d as used herein, refers to a (xe2x95x90O) moiety.
The term xe2x80x9coxy,xe2x80x9d as used herein, refers to a (xe2x80x94Oxe2x80x94) moiety.
The term xe2x80x9csulfamyl,xe2x80x9d as used herein, refers to a xe2x80x94SO2NR94R95 group, wherein R94 and R95 are independently selected from hydrogen, alkyl, aryl, and arylalkyl, as defined herein. Representative examples of sulfamyl include, but are not limited to, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl, phenylaminosulfonyl, benzylaminosulfonyl, and the like.
The term xe2x80x9csulfamylalkyl,xe2x80x9d as used herein, refers to a sulfamyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of sulfamylalkyl include, but are not limited to, (aminosulfonyl)methyl, (dimethylaminosulfonyl)methyl, 2-(aminosulfonyl)ethyl, 3-(aminosulfonyl)propyl, 3-aminosulfonyl-1,1-dimethylpropyl, and the like.
The term xe2x80x9csulfamyl(halo)alkyl,xe2x80x9d as used herein, refers to a sulfamyl group and at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of sulfamyl(halo)alkyl include, but are not limited to, (aminosulfonyl)dichloromethyl, (aminosulfonyl)difluoromethyl, (dimethylaminosulfonyl)difluoromethyl, 2-(aminosulfonyl)-1,1-dichloroethyl, 3-(aminosulfonyl)-1,1-difluoropropyl, 3-aminosulfonyl-1,1-dichloropropyl, 3-(aminosulfonyl)-1,2-difluoropropyl, and the like.
The term xe2x80x9csulfinyl,xe2x80x9d as used herein, refers to a xe2x80x94S(O)xe2x80x94 group.
The term xe2x80x9csulfonyl,xe2x80x9d as used herein, refers to a xe2x80x94SO2xe2x80x94 group.
The term xe2x80x9ctautomer,xe2x80x9d as used herein, refers to a proton shift from one atom of a molecule to another atom of the same molecule.
The term xe2x80x9cthio,xe2x80x9d as used herein, refers to a (xe2x80x94Sxe2x80x94) moiety.
Compounds of the present invention may exist as stereoisomers wherein, asymmetric or chiral centers are present. These stereoisomers are xe2x80x9cRxe2x80x9d or xe2x80x9cSxe2x80x9d depending on the configuration of substituents around the chiral carbon atom. The terms xe2x80x9cRxe2x80x9d and xe2x80x9cSxe2x80x9d used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30. The present invention contemplates various stereoisomers and mixtures thereof and are specifically included within the scope of this invention. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of compounds of the present invention may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.
Tautomers may exist in the compounds of the present invention and are specifically included within the scope of the present invention. The present invention contemplates tautomers due to proton shifts from one atom to another atom of the same molecule generating two or more compounds that are in equilibrium with each other. An example of tautomers of the present invention includes, but is not limited to, 
wherein R1, R2, R3, R6 and R8 are as defined in formula I.
Syn and anti geometric isomers and mixtures thereof may also exist in the compounds of the present invention. Syn and anti geometric isomers and mixtures thereof are specifically included within the scope of this invention. An example of syn and anti geometric isomers of the present invention includes, but is not limited to, 
wherein R1, R2, R3, R6 and R8 are as defined in formula I.
Preferred compounds of formula I include,
4-chloro-N-(1-{[(hydroxyimino)(3-pyridinylamino)methyl]amino}-2,2-dimethylpropyl)benzamide;
4-chloro-N-(1-{[(methoxyimino)(3-pyridinylamino)methyl]amino}-2,2-dimethylpropyl)benzamide;
4-chloro-N-(1-{[{[(4-fluorobenzyl)oxy]imino}(3-pyridinylamino)methyl]amino}-2,2-dimethylpropyl)benzamide;
4-chloro-N-(2,2-dimethyl-1-{[[(methylsulfonyl)imino](3-pyridinylamino)methyl]amino}propyl)benzamide;
4-chloro-N-(1-{[(cyanoimino)(6-fluoro-1H-indol-1-yl)methyl]amino}-2,2-dimethylpropyl)benzamide;
4-chloro-N-(1-{[(cyanoimino)(6-fluoro-1H-benzimidazol-1-yl)methyl]amino}-2,2-dimethylpropyl)benzamide;
3-(4-chlorophenyl)-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-dimethylpropyl)propanamide;
N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-dimethylpropyl)-3-phenylpropanamide;
N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-dimethylpropyl)-2-phenylacetamide;
N-[1-(5-chloro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,2-dimethylpropyl]-Nxe2x80x3-cyano-Nxe2x80x2-(3-pyridinyl)guanidine;
4-(aminosulfonyl)-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-dimethylpropyl)-2-fluorobenzamide;
4-chloro-N-[1-({(cyanoimino)[(4-ethyl-3-pyridinyl)amino]methyl}amino)-2,2-dimethylpropyl]benzamide;
N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-dimethylpropyl)-4-(trifluoromethoxy)benzamide;
4-chloro-N-[1-({(cyanoimino)[(4-ethyl-3-pyridinyl)amino]methyl}amino)-2,2-dimethylpropyl]-2-fluorobenzamide;
4-chloro-N-(1-{[(cyanoimino)(5-pyrimidinylamino)methyl]amino}-2,2-dimethylpropyl)benzamide;
4-chloro-N-(1-{[(cyanoimino)(5-pyrimidinylamino)methyl]amino}-2,2-dimethylpropyl)-2-fluorobenzamide;
N-(1-{[[(4-bromo-3-pyridinyl)amino](cyanoimino)methyl]amino}-2,2-dimethylpropyl)-4-chlorobenzamide;
4-chloro-2-fluoro-N-[2,2,2-trichloro-1-({(cyanoimino)[(4-ethyl-3-pyridinyl)amino]methyl}amino)ethyl]benzamide;
4-chloro-N-(2,2,2-trichloro-1-{[(cyanoimino)(5-pyrimidinylamino)methyl]amino}ethyl)benzamide;
4-chloro-2-fluoro-N-(2,2,2-trichloro-1-{[(cyanoimino)(5-pyrimidinylamino)methyl]amino}ethyl)benzamide;
N-(1-{[[(4-bromo-3-pyridinyl)amino](cyanoimino)methyl]amino}-2,2,2-trichloroethyl)-4-chlorobenzamide;
N-(1-{[[(2-bromo-3-pyridinyl)amino](cyanoimino)methyl]amino}-2,2-dimethylpropyl)-4-chlorobenzamide;
4-chloro-N-[1-({(cyanoimino)[(2-ethyl-3-pyridinyl)amino]methyl}amino)-2,2-dimethylpropyl]benzamide;
N-(1-{[[(5-bromo-4-ethyl-3-pyridinyl)amino](cyanoimino)methyl]amino}-2,2-dimethylpropyl)-4-chlorobenzamide;
4-chloro-N-[1-({(cyanoimino)[(4,5-dibromo-3-pyridinyl)amino]methyl}amino)-2,2-dimethylpropyl]benzamide;
4-chloro-N-(1-{[[(5-chloro-3-pyridinyl)amino](cyanoimino)methyl]amino}-2,2-dimethylpropyl)benzamide;
N-(1-{[[(5-bromo-6-chloro-3-pyridinyl)amino](cyanoimino)methyl]amino}-2,2-dimethylpropyl)-4-chlorobenzamide;
N-(1-{[[(5-bromo-3-pyridinyl)amino](cyanoimino)methyl]amino}-2,2-dimethylpropyl)-4-chlorobenzamide;
N-(1-{[[(6-bromo-3-pyridinyl)amino](cyanoimino)methyl]amino}-2,2-dimethylpropyl)-4-chlorobenzamide;
4-chloro-N-(1-{[(cyanoimino)({5-[(4-fluorophenyl)sulfonyl]-3-pyridinyl}amino)methyl]amino}-2,2-dimethylpropyl)benzamide;
N-(1-{[({5-[(aminoperoxy)sulfanyl]-3-pyridinyl}amino)(cyanoimino)methyl]amino}-2,2-dimethylpropyl)-4-chlorobenzamide;
N-(1-{[[(6-bromo-4-fluoro-3-pyridinyl)amino](cyanoimino)methyl]amino}-2,2-dimethylpropyl)-4-chlorobenzamide;
4-chloro-N-[1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]benzamide;
4-chloro-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}cyclopentyl)benzamide;
4-chloro-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}cyclohexyl)benzamide;
4-chloro-N-[{[(cyanoimino)(3-pyridinylamino)methyl]amino}(2,6-dimethylphenyl)methyl]benzamide;
4-chloro-N-[{[(cyanoimino)(3-pyridinylamino)methyl]amino}(3-pyridinyl)methyl]benzamide;
4-chloro-N-[{[(cyanoimino)(3-pyridinylamino)methyl]amino}(2-pyridinyl)methyl]benzamide;
4-chloro-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2-methyl-2-phenylpropyl)benzamide;
4-chloro-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-3,3-dimethyl-2-oxobutyl)benzamide;
4-chloro-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-3,3,3-trifluoro-2-oxopropyl)benzamide;
4-chloro-N-[1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-3,3,3-trifluoro-2-methyl-2-(trifluoromethyl)propyl]benzamide;
methyl 4-[(4-chlorobenzoyl)amino]-4-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-3,3-dimethylbutanoate;
4-chloro-N-[1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-4-(dimethylamino)-2,2-dimethylbutyl]benzamide;
4-chloro-N-(4-cyano-1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-dimethylbutyl)benzamide;
4-chloro-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-4-methoxy-2,2-dimethylbutyl)benzamide;
4-chloro-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-4-hydroxy-2,2-dimethylbutyl)benzamide;
N-(4-(aminosulfonyl)-1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-dimethylbutyl)-4-chlorobenzamide;
4-chloro-N-[1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-dimethyl-4-(phenylsulfonyl)butyl]benzamide;
4-chloro-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-3-hydroxy-2,2-dimethylpropyl)benzamide;
4-chloro-N-{2,2,2-trichloro-1-[2-(cyanoimino)-3-(3-pyridinyl)imidazolidinyl]ethyl}benzamide;
4-chloro-N-{1-[2-(cyanoimino)-3-(3-pyridinyl)imidazolidinyl]-2,2-dimethylpropyl}benzamide;
2-tert-butyl-3-(4-chlorobenzoyl)-Nxe2x80x2-cyano-N-(3-pyridinyl)-1-imidazolidinecarboximidamide;
N-(4-(aminosulfonyl)-2,2-dichloro-1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}butyl)-4-chlorobenzamide;
4-chloro-N-[4-cyano-1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-bis(trifluoromethyl)butyl]benzamide;
4-chloro-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-difluoro-4-oxopentyl)benzamide;
4-chloro-N-(1-{[2-cyano-1-(3-pyridinylamino)ethenyl]amino}-2,2-dimethylpropyl)benzamide;
4-chloro-N-{1-[[(cyanoimino)(3-pyridinylamino)methyl](hydroxy)amino]-2,2-dimethylpropyl}benzamide;
4-chloro-N-(2,2,2-trichloro-1-{[2-nitro-1-(3-pyridinylamino)ethenyl]amino}ethyl)benzamide;
4-chloro-N-(2,2,2-trichloro-1-{[2-cyano-1-(3-pyridinylamino)ethenyl]amino}ethyl)benzamide and pharmaceutically acceptable salts, amides, esters, or produrgs thereof.
More preferred compounds of formula I include,
4-methyl-N-(2,2,2-trifluoro-1-{[(3-pyridinylamino)carbothioyl]amino}ethyl)benzamide;
4-methyl-N-{2,2,2-trifluoro-1-[(2-toluidinocarbothioyl)amino]ethyl}benzamide;
4-methyl-N-(2,2,2-trifluoro-1-{[(4-fluoroanilino)carbothioyl]amino}ethyl)benzamide;
4-methyl-N-(2,2,2-trifluoro-1-{[(3-nitroanilino)carbothioyl]amino}ethyl)benzamide;
4-methyl-N-[2,2,2-trifluoro-1-({[2-fluoro-3-(trifluoromethyl)anilino]carbothioyl)amino}ethyl]benzamide;
4-methyl-N-(2,2,2-trifluoro-1-{[(4-methoxyanilino)carbothioyl]amino}ethyl)benzamide;
N-[1-({[(6-chloro-3-pyridinyl)amino]carbothioyl}amino)-2,2,2-trifluoroethyl]-4-methylbenzamide;
4-methyl-N-(2,2,2-trifluoro-1-{[(2-methoxyanilino)carbothioyl]amino}ethyl)benzamide;
N-{1-[(anilinocarbothioyl)amino]-2,2,2-trifluoroethyl}-4-methylbenzamide;
4-methyl-N-{2,2,2-trifluoro-1-[(4-toluidinocarbothioyl)amino]ethyl}benzamide;
4-methyl-N-(2,2,2-trifluoro-1-{[(2-fluoroanilino)carbothioyl]amino}ethyl)benzamide;
4-methyl-N-(2,2,2-trifluoro-1-{[(3-methoxyanilino)carbothioyl]amino}ethyl)benzamide;
4-methyl-N-(2,2,2-trifluoro-1-{[(3-fluoroanilino)carbothioyl]amino}ethyl)benzamide;
N-(1-{[(2,5-difluoroanilino)carbothioyl]amino}-2,2,2-trifluoroethyl)-4-methylbenzamide;
N-(1-{[(2,4-difluoroanilino)carbothioyl]amino}-2,2,2-trifluoroethyl)-4-methylbenzamide;
4-methyl-N-{2,2,2-trifluoro-1-[(3-toluidinocarbothioyl)amino]ethyl}benzamide;
N-(1-{[(2,6-difluoroanilino)carbothioyl]amino}-2,2,2-trifluoroethyl)-4-methylbenzamide;
N-(1-{[(2,3-difluoroanilino)carbothioyl]amino)-2,2,2-trifluoroethyl)-4-methylbenzamide;
4-chloro-N-(2,2,2-trifluoro-1-{[(3-pyridinylamino)carbothioyl]amino}ethyl)benzamide;
N-{1-[(anilinocarbothioyl)amino]-2,2,2-trifluoroethyl}-4-chlorobenzamide;
4-chloro-N-(2,2,2-trifluoro-1-{[(2-fluoroanilino)carbothioyl]amino}ethyl)benzamide;
N-(2,2-dimethyl-1-{[(3-pyridinylamino)carbothioyl]amino}propyl}-4-methylbenzamide;
N-((1R)-2,2-dimethyl-1-{[(3-pyridinylamino)carbothioyl]amino}propyl)-4-methylbenzamide;
N-((1S)-2,2-dimethyl-1-{[(3-pyridinylamino)carbothioyl]amino}propyl)-4-methylbenzamide;
N-(2,2-dimethyl-1-{[(3-nitroanilino)carbothioyl]amino}propyl)-4-methylbenzamide;
N-(2,2-dimethyl-1-{[(3-pyridinylamino)carbothioyl]amino}propyl)-2-methylbenzamide;
4-chloro-N-(2,2-dimethyl-1-{[(3-pyridinylamino)carbothioyl]amino}propyl)benzamide;
N-(2,2-dimethyl-1-{[(3-pyridinylamino)carbothioyl]amino}propyl)benzamide;
4-methyl-N-(1-{[(3-nitroanilino)carbothioyl]amino}ethyl)benzamide;
4-methyl-N-(1-{[(3-nitroanilino)carbothioyl]amino}-2-phenylethyl)benzamide;
N-((1R)-2-(tert-butoxy)-1-{[(3-nitroanilino)carbothioyl]amino)ethyl)-4-methylbenzamide;
N-(2-fluoro-1-{[(3-nitroanilino)carbothioyl]amino I ethyl)-4-methylbenzamide;
4-methyl-N-[{[(3-nitroanilino)carbothioyl]amino}(phenyl)methyl]benzamide;
4-methyl-N-(phenyl{[(3-pyridinylamino)carbothioyl]amino}methyl)benzamide;
4-methyl-N-(2-methyl-1-{[(3-pyridinylamino)carbothioyl]amino}propyl)benzamide;
4-methyl-N-((1R,2S)-2-methyl-1-{[(3-pyridinylamino)carbothioyl]amino}butyl)benzamide;
4-methyl-N-{2,2,2-trichloro-1-[3-(3-fluorophenyl)-2-thioxo-1-imidazolidinyl]ethyl}benzamide;
4-methyl-N-(2,2,2-trichloro-1-{[(3-pyridinylamino)carbonyl]amino}ethyl)benzamide;
2-methyl-N-(2,2,2-trichloro-1-{[(3-pyridinylamino)carbonyl]amino}ethyl)benzamide;
N-(2,2,2-trichloro-1-{[(3-pyridinylamino)carbonyl]amino}ethyl)benzamide;
4-chloro-N-(2,2,2-trichloro-1-{[(3-pyridinylamino)carbonyl]amino}ethyl)benzamide;
N-{1-[(anilinocarbonyl)amino]-2,2,2-trichloroethyl}-4-methylbenzamide;
4-methyl-N-(2,2,2-trichloro-1-{[(2-fluoroanilino)carbonyl]amino}ethyl)benzamide;
4-methyl-N-(2,2,2-trichloro-1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}ethyl)benzamide;
4-chloro-N-(2,2,2-trichloro-1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}ethyl)benzamide;
N-(1-{[anilino(cyanoimino)methyl]amino}-2,2,2-trichloroethyl)-4-methylbenzamide;
4-methyl-N-(2,2,2-trichloro-1-{[(cyanoimino)(2-fluoroanilino)methyl]amino}ethyl)benzamide;
4-methyl-N-(2,2,2-trichloro-1-{[(cyanoimino)(5-pyrimidinylamino)methyl]amino}ethyl)benzamide;
N-(2,2,2-trichloro-1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}ethyl)benzamide;
2-methyl-N-(2,2,2-trichloro-1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}ethyl)benzamide;
N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-dimethylpropyl)-4-methylbenzamide;
4-chloro-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-dimethylpropyl)benzamide;
N-(1-{[(cyanoimino)(3-fluoroanilino)methyl]amino}-2,2-dimethylpropyl)-4-methylbenzamide;
4-chloro-N-[{[(cyanoimino)(3-pyridinylamino)methyl]amino}(cyclopropyl)methyl]benzamide;
N-(1-{[[(6-chloro-3-pyridinyl)amino](cyanoimino)methyl]amino}-2,2-dimethylpropyl)-4-methylbenzamide;
4-chloro-N-[{[(cyanoimino)(3-fluoroanilino)methyl]amino}(3-thienyl)methyl]benzamide;
(xe2x88x92) N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-dimethylpropyl)-4-methylbenzamide;
(+) N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-dimethylpropyl)-4-methylbenzamide;
4-chloro-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2-ethylbutyl)benzamide;
4-chloro-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-3-methylbutyl)benzamide;
4-chloro-N-[{[(cyanoimino)(3-pyridinylamino)methyl]amino}(cyclohexyl)methyl]benzamide;
4-chloro-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-3,3-dimethylbutyl)benzamide;
4-chloro-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2-methylpropyl)benzamide;
4-chloro-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2,2-trifluoroethyl)benzamide;
4-chloro-N-(4-cyano-1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-diethylbutyl)benzamide;
4-chloro-N-[1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2-(2,6,6-trimethyl-1-cyclohexen-1-yl)ethyl]benzamide;
4-chloro-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-dimethyl-4-pentenyl)benzamide;
4-chloro-N-(2-ethyl-1-{[2-nitro-1-(3-pyridinylamino)ethenyl]amino}butyl)benzamide;
4-chloro-N-(1-{[(cyanoimino)(2-fluoroanilino)methyl]amino}-2,2-dimethylpropyl)benzamide;
4-chloro-N-(1-{[(cyanoimino)(3-fluoroanilino)methyl]amino}-2,2-dimethylpropyl)benzamide;
4-chloro-N-[1-({(cyanoimino)[3-(trifluoromethyl)anilino]methyl}amino}2,2-dimethylpropyl]benzamide;
4-chloro-N-(1-{[(cyanoimino)(3,5-difluoroanilino)methyl]amino}-2,2-dimethylpropyl)benzamide;
4-chloro-N-(1-{[(cyanoimino)(2,5-difluoroanilino)methyl]amino}-2,2-dimethylpropyl)benzamide;
4-chloro-N-(1-{[(cyanoimino)(2,6-difluoroanilino)methyl]amino}-2,2-dimethylpropyl)benzamide;
4-chloro-N-(1-{[(cyanoimino)(3-chloroanilino)methyl]amino}-2,2-dimethylpropyl)benzamide;
4-chloro-N-(1-{[(cyanoimino)(3-methoxyanilino)methyl]amino}-2,2-dimethylpropyl)benzamide;
4-chloro-N-(1-{[[(2-chlorobenzyl)amino](cyanoimino)methyl]amino}-2,2-dimethylpropyl)benzamide;
4-chloro-N-(1-{[[(3-chlorobenzyl)amino](cyanoimino)methyl]amino}-2,2-dimethylpropyl)benzamide;
4-chloro-N-(1-{[[(4-chlorobenzyl)amino](cyanoimino)methyl]amino}-2,2-dimethylpropyl)benzamide;
4-chloro-N-[1-({(cyanoimino)[(3-pyridinylmethyl)amino]methyl}amino}-2,2-dimethylpropyl]benzamide;
4-chloro-N-[1-({(cyanoimino)[(4-pyridinylmethyl)amino]methyl}amino)-2,2-dimethylpropyl]benzamide;
4-chloro-N-[1-({(cyanoimino)[(2-pyridinylmethyl)amino]methyl}amino)-2,2-dimethylpropyl]benzamide;
4-chloro-N-(1-{[(cyanoimino)(3-quinolinylamino)methyl]amino}-2,2-dimethylpropyl)benzamide;
4-chloro-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}propyl)benzamide;
4-chloro-N-({[(cyanoimino)(3-pyridinylamino)methyl]amino}methyl)benzamide;
(xe2x88x92) 4-chloro-N-(4-cyano-1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-diethylbutyl)benzamide;
(+) 4-chloro-N-(4-cyano-1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-diethylbutyl)benzamide;
(+) 4-chloro-N-[1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2-(2,6,6-trimethyl-1-cyclohexen-1-yl)ethyl]benzamide;
(xe2x88x92) 4-chloro-N-[1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2-(2,6,6-trimethyl-1-cyclohexen-1-yl)ethyl]benzamide;
(xe2x88x92) 4-chloro-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-dimethyl-4-pentenyl)benzamide;
(+) 4-chloro-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-dimethyl-4-pentenyl)benzamide;
4-chloro-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-3,3-dimethyl-4-pentenyl)benzamide;
4-chloro-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2-cyclohexyl-2-methylpropyl)benzamide;
4-chloro-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-dimethylhexyl)benzamide;
N-(2-(1-adamantyl)-1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}ethyl)-4-chlorobenzamide;
N-(2,2-bis[(allyloxy)methyl]-1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}butyl)-4-chlorobenzamide;
4-chloro-N-[1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-3-(dimethylamino)-2,2-dimethylpropyl]benzamide;
tert-butyl (2R)-2-((R)-[(4-chlorobenzoyl)amino]{[(cyanoimino)(3-pyridinylamino)methyl]amino}methyl)-1-pyrrolidinecarboxylate;
4-chloro-N-[1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-3-(methylsulfanyl)propyl]benzamide;
N-(1-adamantyl {[(cyanoimino)(3-pyridinylamino)methyl]amino}methyl)-4-chlorobenzamide;
4-chloro-N-[{[(cyanoimino)(3-pyridinylamino)methyl]amino}(5-ethyl-1,3-dioxan-5-yl)methyl]benzamide;
4-chloro-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-dimethyl-3-phenylpropyl)benzamide;
N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-dimethylpropyl)-4-iodobenzamide;
N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-dimethylpropyl)-4-(2-furyl)benzamide;
4-bromo-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-dimethylpropyl)benzamide;
4-chloro-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-dimethylpropyl)-2-fluorobenzamide;
N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-dimethylpropyl)-4-fluorobenzamide;
N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-dimethylpropyl)-3-methylbenzamide;
N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-dimethylpropyl)-2-methylbenzamide;
N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-dimethylpropyl)-3,5-difluorobenzamide;
4-chloro-N-{1-[[(cyanoimino)(3-pyridinylamino)methyl](methyl)amino]-2,2-dimethylpropyl}benzamide;
(xe2x88x92) 4-chloro-N-(2,2,2-trichloro-1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}ethyl)benzamide;
(+) 4-chloro-N-(2,2,2-trichloro-1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}ethyl)benzamide;
4-iodo-N-(2,2,2-trichloro-1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}ethyl)benzamide;
4-chloro-N-(2,2-dichloro-1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}pentyl)benzamide;
4-chloro-N-(2,2-dichloro-1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}propyl)benzamide;
(xe2x88x92) 4-chloro-N-(2,2-dichloro-1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}propyl)benzamide;
(+) 4-chloro-N-(2,2-dichloro-1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}propyl)benzamide;
3-chloro-N-(2,2-dichloro-1-{[(cyanoimino)(3-pyridinylamino)methyl]amino)propyl)benzamide;
N-(2,2-dichloro-1-{[(cyanoimino)(3-pyridinylamino)methyl]amino propyl}-3,5-difluorobenzamide;
4-chloro-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2,3,3,3-pentafluoropropyl)benzamide;
3-chloro-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2,3,3,3-pentafluoropropyl)benzamide;
4-chloro-N-(1-{[(nitroimino)(3-pyridinylamino)methyl]amino}-2,2-dimethylpropyl)benzamide;
4-chloro-N-(1-{[(nitroimino)(3-pyridinylamino)methyl]amino}-3,3-dimethylbutyl)benzamide;
(+) 4-chloro-N-(1-{[(nitroimino)(3-pyridinylamino)methyl]amino}-3,3-dimethylbutyl)benzamide;
(xe2x88x92) 4-chloro-N-(1-{[(nitroimino)(3-pyridinylamino)methyl]amino}-3,3-dimethylbutyl)benzamide;
4-chloro-N-(1-{[(nitroimino)(3-pyridinylamino)methyl]amino}-2,2-dimethyl-4-pentenyl)benzamide;
4-chloro-N-(1-{[(nitroimino)(3-pyridinylamino)methyl]amino}-2,2-dimethyl-3-phenylpropyl)benzamide;
4-chloro-N-[1-{[(nitroimino)(3-pyridinylamino)methyl]amino}-2-(2,6,6-trimethyl-1-cyclohexen-1-yl)ethyl]benzamide;
4-chloro-N-(1-{[(nitroimino)(3-pyridinylamino)methyl]amino}-2-cyclohexyl-2-methylpropyl)benzamide;
N-(2,2-bis[(allyloxy)methyl]-1-{[(nitroimino)(3-pyridinylamino)methyl]amino}butyl)-4-chlorobenzamide;
4-chloro-N-(4-cyano-1-{[(nitroimino)(3-pyridinylamino)methyl]amino}-2,2-diethylbutyl)benzamide;
4-chloro-N-(1-{[(nitroimino)(3-pyridinylamino)methyl]amino}-3,3-dimethyl4-pentenyl)benzamide;
N-(2-(1-adamantyl)-1-{[(nitroimino)(3-pyridinylamino)methyl]amino}ethyl}4-chlorobenzamide;
N-(1-[(nitroimino)(3-pyridinylamino)methyl]amino-2,2-dimethylpropyl)-4-phenylbenzamide;
4-chloro-N-(2,2-dichloro-1-{[(nitroimino)(3-pyridinylamino)methyl]amino}pentyl)benzamide;
4-chloro-N-(2,2-dichloro-1-{[(nitroimino)(3-pyridinylamino)methyl]amino}propyl)benzamide;
3-chloro-N-(2,2-dichloro-1-{[(nitroimino)(3-pyridinylamino)methyl]amino}propyl)benzamide;
4-chloro-N-(2,2-dimethyl-1-{[[(phenylsulfonyl)imino](3-pyridinylamino)methyl]amino}propyl)benzamide;
4-chloro-N-(3,3-dimethyl-1-{[[(phenylsulfonyl)imino](3-pyridinylamino)methyl]amino}butyl)benzamide;
4-chloro-N-{2,2-dimethyl-1-[((3-pyridinylamino){[(trifluoromethyl)sulfonyl]imino}methyl)amino]propyl}benzamide;
4-chloro-N-{3,3-dimethyl-1-[((3-pyridinylamino){[(trifluoromethyl)sulfonyl]imino}methyl)amino]butyl}benzamide;
N-(1-{[[(aminosulfonyl)imino](3-pyridinylamino)methyl]amino}-2,2-dimethylpropyl)-4-chlorobenzamide;
N-(1-{[[(aminosulfonyl)imino](3-pyridinylamino)methyl]amino}-3,3-dimethylbutyl)-4-chlorobenzamide;
4-chloro-N-(1-{[{[(dimethylamino)sulfonyl]imino}(3-pyridinylamino)methyl]amino}-2,2-dimethylpropyl)benzamide;
4-chloro-N-(1-{[{[(dimethylamino)sulfonyl]imino}(3-pyridinylamino)methyl]amino}-3,3-dimethylbutyl)benzamide;
4-chloro-N-(1-{[(2-fluoroanilino)carbonyl]amino}-2,2-dimethylpropyl)benzamide;
4-iodo-N-(2,2,2-trichloro-1-{[(3-pyridinylamino)carbothioyl]amino}ethyl)benzamide;
3-phenyl-N-(2,2,2-trichloro-1-{[(3-nitroanilino)carbothioyl]amino}ethyl)propanamide;
4-chloro-N-(2,2-dimethyl-1-{[2-nitro-1-(3-pyridinylamino)ethenyl]amino}propyl)benzamide;
4-chloro-N-(2,2-dichloro-1-{[2-nitro-1-(3-pyridinylamino)ethenyl]amino}pentyl)benzamide;
4-chloro-N-(1-{[2,2-dicyano-1-(3-pyridinylamino)vinyl]amino}-2,2-dimethylpropyl)benzamide;
3-chloro-N-(2,2-dichloro-1-{[[(6-chloro-3-pyridinyl)amino](cyanoimino)methyl]amino}propyl)benzamide;
N-(2,2-dichloro-1-{[[(6-chloro-3-pyridinyl)amino](cyanoimino)methyl]amino}propyl)-4-methylbenzamide;
N-{2,2-dichloro-1-[((cyanoimino)){[6-(trifluoromethyl)-3-pyridinyl]amino}methyl)amino]propyl}-3,5-difluorobenzamide;
N-(2,2-dichloro-1-{[[(6-chloro-3-pyridinyl)amino](cyanoimino)methyl]amino}propyl)-3-fluorobenzamide;
N-[2,2-dichloro-1-({(cyanoimino)[(2-methoxy-3-pyridinyl)amino]methyl}amino)propyl]-3,5-difluorobenzamide;
4-chloro-N-{2,2-dichloro-1-[((cyanoimino){[6-(trifluoromethyl)-3-pyridinyl]amino}methyl)amino]propyl}benzamide;
3-chloro-N-{2,2-dichloro-1-[((cyanoimino){[6-(trifluoromethyl)-3-pyridinyl]amino}methyl)amino]propyl}benzamide;
4-chloro-N-(2,2-dichloro-1-{[[(6-chloro-3-pyridinyl)amino](cyanoimino)methyl]amino}propyl)benzamide;
(xe2x88x92) 4-chloro-N-(2,2-dichloro-1-{[[(6-chloro-3-pyridinyl)amino](cyanoimino)methyl]amino}propyl)benzamide;
(+) 4-chloro-N-(2,2-dichloro-1-{[[(6-chloro-3-pyridinyl)amino](cyanoimino)methyl]amino}propyl)benzamide;
4-bromo-N-(2,2-dichloro-1-{[[(6-chloro-3-pyridinyl)amino](cyanoimino)methyl]amino}propyl)benzamide;
3,5-dichloro-N-[2,2-dichloro-1-({(cyanoimino)[(2-methoxy-3-pyridinyl)amino]methyl}amino)propyl]benzamide;
3,5-dichloro-N-(2,2-dichloro-1-{[[(6-chloro-3-pyridinyl)amino](cyanoimino)methyl]amino}propyl)benzamide;
N-(2,2-dichloro-1-{[[(6-chloro-3-pyridinyl)amino](cyanoimino)methyl]amino}propyl)-3,5-difluorobenzamide;
4-bromo-N-(2,2-dichloro-1-{[[(6-chloro-3-pyridinyl)amino](cyanoimino)methyl]amino}propyl)benzamide;
4-chloro-N-(2,2-dichloro-1-{[[(2-chloro-3-pyridinyl)amino](cyanoimino)methyl]amino}propyl)benzamide;
3-chloro-N-(2,2-dichloro-1-{[(cyanoimino)(3-fluoroanilino)methyl]amino}propyl)benzamide;
N-(2,2-dichloro-1-{[[(6-chloro-3-pyridinyl)amino](cyanoimino)methyl]amino}propyl)-3-methylbenzamide;
N-(2,2-dichloro-1-{[[(6-chloro-3-pyridinyl)amino](cyanoimino)methyl]amino}propyl)-4-(trifluoromethyl)benzamide;
3-chloro-N-(2,2-dichloro-1-{[(cyanoimino)(2-fluoroanilino)methyl]amino}propyl)benzamide;
N-(2,2-dichloro-1-{[[(6-chloro-3-pyridinyl)amino](cyanoimino)methyl]amino}propyl)-4-fluorobenzamide;
3-chloro-N-[2,2-dichloro-1-({(cyanoimino)[(2-methoxy-3-pyridinyl)amino]methyl}amino)propyl]benzamide;
4-chloro-N-(2,2-dichloro-1-{[(cyanoimino)(2-fluoroanilino)methyl]amino}propyl)benzamide;
4-chloro-N-[2,2-dichloro-1-({(cyanoimino)[(2-methoxy-3-pyridinyl)amino]methyl}amino)propyl]benzamide;
3-chloro-N-[2,2-dichloro-1-({(cyanoimino)[(6-fluoro-3-pyridinyl)amino]methyl}amino)propyl]benzamide;
N-(2,2-dichloro-1-{[[(6-chloro-3-pyridinyl)amino](cyanoimino)methyl]amino}propyl)-3,5-dimethoxybenzamide;
N-(2,2-dichloro-1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}propyl3-methylbenzamide;
4-chloro-N-[2,2-dichloro-1-({(cyanoimino)[(6-fluoro-3-pyridinyl)amino]methyl}amino)propyl]benzamide;
4-chloro-N-(2,2-dichloro-1-{[(cyanoimino)(2-methoxyanilino)methyl]amino}propyl)benzamide;
3-chloro-N-[2,2-dichloro-1-({(cyanoimino)[(6-methoxy-3-pyridinyl)amino]methyl}amino)propyl]benzamide;
N-{2,2-dichloro-1-[((cyanoimino){[6-(trifluoromethyl)-3-pyridinyl]amino}methyl)amino]propyl}-3,5-dimethoxybenzamide;
4-chloro-N-{2,2-dichloro-1-[((cyanoimino){[2-methyl-6-(trifluoromethyl)-3-pyridinyl]amino}methyl)amino]propyl}benzamide;
N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-dimethylpropyl)-4-fluoro-3-(trifluoromethyl)benzamide;
(+) 4-chloro-N-{3,3-dimethyl-1-[((3-pyridinylamino){[(trifluoromethyl)sulfonyl]imino}methyl)amino]butyl}benzamide;
(xe2x88x92) 4-chloro-N-{3,3-dimethyl-1-[((3-pyridinylamino){[(trifluoromethyl)sulfonyl]imino}methyl)amino]butyl}benzamide;
4-bromo-N-{3,3-dimethyl-1-[((3-pyridinylamino){[(trifluoromethyl)sulfonyl]imino}methyl)amino]butyl}benzamide;
N-{3,3-dimethyl-1-[((3-pyridinylamino){[(trifluoromethyl)sulfonyl]imino}methyl)amino]butyl}-4-(trifluoromethyl)benzamide;
3,5-dichloro-N-{2,2-dichloro-1-[((3-pyridinylamino){[(trifluoromethyl)sulfonyl]imino}methyl)amino]propyl}benzamide;
N-{2,2-dichloro-1-[((3-pyridinylamino){[(trifluoromethyl)sulfonyl]imino}methyl)amino]propyl}4-(trifluoromethyl)benzamide;
N-(2,2-dichloro-1-{[[(6-chloro-3-pyridinyl)amino](cyanoimino)methyl]amino}propyl)-2-thiophenecarboxamide; and
N-(2,2-dichloro-1-{[[(6-chloro-3-pyridinyl)amino](cyanoimino)methyl]amino}propyl)nicotinamide and pharmaceutically acceptable salts, esters, amides, or prodrugs thereof.
The following abbreviations are used: Ac for acetyl; (Boc)2O for di-tert-butyl dicarbonate; DCC for dicyclohexylcarbodiimide; DMF for N,N-dimethylformamide; DMSO for dimethyl sulfoxide; EDCI for 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride; Et for ethyl; Et3N for triethylamine; EtOH for ethanol; Me for methyl; MeOH for methanol; NaHMDS for sodium bis(trimethylsilyl)amide; i-Pr for isopropyl; pyr for pyridine; Tf for triflate or xe2x80x94OS(O)2CF3; THF for tetrahydrofuran; and p-TsOH for para-toluenesulfonic acid monohydrate.
The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes and methods which illustrate a means by which the compounds of the invention can be prepared.
The compounds of this invention may be prepared by a variety of synthetic routes. Representative procedures are shown in Schemes 1-25. 
As shown in Scheme 1, urea and thiourea aminals of general formula (6), wherein R1, R3, R4, and R6 are as defined in formula I, R2 is haloalkyl (such as CCl3 or CF3), and X is O or S, may be prepared using the strategy outlined above. Amides of general formula (1) may be treated with xcex1-haloaldehyde hydrates or xcex1-halohemiacetals of general formula (2), wherein R is H and Rxe2x80x2 is H or alkyl, such as 2,2,2-trichloro-1,1-ethanediol or 1-ethoxy-2,2,2-trifluoro-1-ethanol, followed by addition of a chlorinating agent such as thionyl chloride and a base such as pyridine to provide chloroamides of general formula (3). The chloroamides (3) may be treated with potassium cyanate or potassium thiocyanate to provide isocyanates or isothiocyanates respectively of general formula (4). The isocyanates or isothiocyanates (4) may be treated with amines of general formula (5) in the presence of a base such as diisopropylethylamine to provide urea and thiourea aminals of general formula (6). 
As shown in Scheme 2, urea and thiourea aminal derivatives of general formula (9), wherein R1, R3, and R4, are as defined in formula I, R2 is haloalkyl (such as CCl3 or CF3), and X is O or S, may be prepared using the above strategy. Urea and thiourea aminals of general formula (7), wherein Rxe2x80x3 is alkoxy, may be prepared following the strategy described in Scheme 1. Urea and thiourea aminals of general formula (7) may be treated with an acid such as hydrobromic acid to provide primary amines of general formula (8). Amines of general formula (8) may be treated with acid chlorides in the presence of a base such as diisopropylethylamine to provide urea and thiourea aminals of general formula (9). 
Urea and thiourea aminals of general formula (12), wherein R1, R3, and R6 are as defined in formula I, R2 is haloalkyl (such as CCl3 or CF3), and X is O or S, may be prepared as described in Scheme 3. Chloroamides of general formula (3) may be treated with ammonia to provide aminoamides of general formula (10). The aminoamides (10) may be treated with an isocyanate or an isothiocyanate of general formula (11), wherein X is O or S, to provide urea and thiourea aminals of general formula (12). 
Urea and thiourea aminals of general formula (16) wherein R1 and R3 are as defined in formula I, R2 is haloalkyl (such as CCl3 or CF3), and X is O or S, may be prepared as described in scheme 4. Amines of general formula (13) may be treated with 1,3-oxazolidin-2-one as described in (Poindexter et al., J. Org. Chem. (1992), 57, 6257) to provide primary amines of general formula (14) which may be cyclized to ureas or thioureas of general formula (15) with carbonyl or thiocarbonyl transfer reagents (such as carbonyldiimidazole or thiocarbonyldiimidazole) in the presence of a base such as triethylamine. Cyclic ureas or thioureas of general formula (15) may be treated with a strong base such as sodium bis(trimethylsilyl)amide (NaHMDS) followed by treatment with chloroamides of general formula (3) to provide urea and thiourea aminals of general formula (16). 
A general method for preparing urea aminals from thiourea aminals is described in Scheme 5. Thiourea aminals of general formula (17) may be treated with an oxidizing agent such as hydrogen peroxide in a protic solvent such as acetic acid to provide urea aminals of general formula (18) wherein R1, R2, R3, R4, R5, and R6 are as defined in formula I. 
A general method for preparing guanidine aminals from thiourea aminals is described in Scheme 6. Thiourea aminals of general formula (17) may be treated with a dehydrating agent such as DCC followed by addition of amines of general formula (19), prepared as described in (Scharpenberg, Chem. Ber. (1973), 106, 1881), in the presence of a Lewis acid such as titanium isopropoxide to provide guanidine aminals of general formula (20) wherein R1, R2, R3, R4, R5, R6 and R8 are as defined in formula I. 
As shown in Scheme 7, guanidine aminals of general formula (25), wherein R1, R2, R3, R4, and R8 are as defined in formula I, may be prepared by using the above strategy. Aminoacetamides of general formula (21) may be treated with acid chlorides in the presence of a base such as pyridine or triethylamine to provide the corresponding acylaminoamides of general formula (22). The acylaminoamides (22) may undergo a Hofmann rearrangement as described in (Wallis and Lane, Org. React. (1946), 3, 267-306, and references contained therein) with reagents such as iodosobenzene diacetate as described in (Loudon et al., J. Org. Chem. (1984), 49, 4272); (Loudon and Boutin J. Org. Chem. (1984), 49, 4277); (Chan et al., Synth. Commun. (1988), 53, 5158) to provide aminoamides of general formula (23), which may be typically isolated as their hydrochloride salts. The aminoamides (23) may be treated with thioureas of general formula (24), prepared as described in (Solimar, J.Med.Chem. (1979), 22, 321; and Ulrich, Tetrahedron (1966), 22, 1565) to provide guanidine aminals of general formula (25). An alternate approach for preparation of cyanoguanidine aminals of general formula (25), wherein R8 is cyano, may be used. Aminoamides of general formula (23) may be treated with cyanothioureas of general formula (24), wherein R8 is cyano, in the presence of a base such as diisopropylethylamine and a suitable activating agent such as EDCI to provide cyanoguanidine aminals of general formula (25). 
An alternate route to guanidine aminals of general formula (20), wherein R1, R2, R3, R4, R6 and R8 are as defined in formula I and R5 is H, is shown in Scheme 8. A three-component condensation including benzotriazole, aldehydes of general formula (26), and amides of general formula (1) in the presence of an acid catalyst such as p-toluenesulfonic acid monohydrate as described in (Katritzky et al., J. Org. Chem. (1990), 55, 2206); (Katritzky; Chem. Rev. (1998), 98, 409); (Katritzky; J. Heterocyclic Chem. (1996), 33, 1935) provides benzotriazole adducts of general formula (27). Nucleophilic displacement of the benzotriazole moiety as described in (Katritzky et al., J. Org. Chem. (1990), 55, 2206); (Katritzky, Chem. Rev. (1998), 98, 409); (Katritzky, J. Heterocyclic Chem. (1996), 33, 1935) with ammonia in an alcoholic solvent such as methanol provides aminoamides of general formula (10). The aminoamides (10) may be treated with thioureas of general formula (24) in the presence of a base such as diisopropylethylamine and a suitable activating agent such as EDCI to provide guanidine aminals of general formula (20). 
As shown in Scheme 9, urea and thiourea aminals of general formula (6), wherein R1, R2, R3, R4 and R6 are as defined in formula I and X is O or S, may be prepared by treating benzotriazole adducts of general formula (27) with potassium cyanate or potassium thiocyanate to provide isocyanates or isothiocyantes of general formula (4). Isocyanates or isothiocyanates of general formula (4) may be treated with amines of general formula (5) in the presence of a base such as diisopropylethylamine to provide urea and thiourea aminals of general formula (6). 
As shown in Scheme 10, cyanoguanidine aminals of general formula (29), wherein R1, R2, R3 and R6 are as defined in formula I, may be prepared by using a strategy that employs a two-step sequence. Cyanoguanidines of general formula (28) are first prepared either by Path A or Path B. In path A, amines of general formula (13) are treated with sodium dicyanamide as described in (Tilley et al., Helv. Chim. Acta. (1980), 63, 841); (Jones et al., J. Heterocyclic Chem. (1994), 31, 1681) to provide cyanoguanidines of general formula (28). In Path B, isothiocyanates of general formula (11) are treated in succession with cyanamide, a sodium base such as sodium hydride, an electrophile such as methyl iodide, and ammonia in a polar aprotic solvent such as methanol as described in (Fairfall and Peak; J. Chem. Soc. (1955), 796) to provide cyanoguanidines of general formula (28). The cyanoguanidines (28) are then treated with benzotriazole adducts of general formula (27) in the presence of a base such as potassium carbonate to provide cyanoguanidine aminals of general formula (29). 
Functionality may be introduced onto the guanidine nitrogen (R5) by the synthetic sequence described in Scheme 11. Thioureas of general formula (24) may be treated with a sodium base such as sodium hydride and then alkylated with electrophiles such as methyl iodide to provide methyl carbamimidothioates of general formula (30). Methyl carbamimidothioates (30) may be treated with amines of general formula (31) to provide guanidines of general formula (32) which are then further reacted with benzotriazole adducts of general formula (27) in the presence of a base such as potassium carbonate to provide guanidine aminals of general formula (20) wherein R1, R2, R3, R4, R5, R6, and R8 are as defined in formula I. 
As shown in Scheme 12, geminally-substituted products of general formula (36) wherein R1, R3, R4, R5, R7, and R8 are as defined in formula I and R2 is the same as R7 or R2 and R7 taken together with the carbon atom to which they are attached, together form a 5 or 6 membered carbocyclic ring, may be prepared using the above strategy and as described in (Steglich, Chem. Ber. (1974), 107, 1488); (Burger, J. Fluorine Chem. (1982), 20, 813). Optionally substituted primary amides may be treated with symmetrical ketones of general formula (34) in the presence of a dehydrating agent such as trifluoroacetic anhydride and a base such as pyridine to provide symmetrical imines of general formula (35). The symmetrical imines (35) may be treated with guanidines of general formula (32) in the presence of a base such as triethylamine to provide geminally-substituted compounds of general formula (36). 
Guanidine aminals of general formula (41), wherein R1, R2, R3, R4, and R8 are as defined in formula I and J and K are as defined in formula IV, may be prepared using the strategy described in Scheme 13. Diamino compounds of general formula (37), such as 1,2-ethanediamine, may be condensed with aldehydes of general formula (26) in the presence of molecular sieves to provide 2-substituted imidazolidines of general formula (38). Monoprotection, such as with di-tert-butyl dicarbonate, followed by acylation may provide 2-substituted imidazolidines of general formula (39). Removal of the protecting group provides secondary amines of general formula (40). The secondary amines (40) may be treated with thioureas (24) in the presence of a dehydrating agent such as EDCI to provide guanidine aminals of general formula (41). 
As shown in Scheme 14, ureas and thioureas of general formula (42) wherein R1, R2, R3, and R4 are as defined in formula I, X is O or S. and J and K are as defined in formula IV, may be prepared by treating amines of general formula (40) with an isocyanate or isothiocyanate of general formula (11). 
As shown in Scheme 15, cyanoguanidines of general formula (46) wherein R2, R3, and R6 are as defined in formula I, Y and Z are independently selected from CH and N, and A, B, and D are independently selected from hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfinyl, alkylsulfonyl, alkynyl, arylalkoxycarbonyl, cyano, halogen, haloalkyl, haloalkoxy, nitro, sulfamyl, and xe2x80x94NRARB wherein RA and RB are as defined in formula I, may be prepared by treating heterocycles of general formula (43) with diphenyl cyanocarbonimidate (44) as described in (Atwal et al., J. Med. Chem. (1998), 41, 271) to provide cyanocarboximidates of general formula (45). The cyanocarboximidates (45) may be treated with amines of general formula (10) to provide cyanoguanidines of general formula (46). 
As shown in Scheme 16, guanidine aminals of general formula (49) wherein R1, R2, R4, R5, and R8 are as defined in formula I, L, M, and Q are independently selected from hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfinyl, alkylsulfonyl, alkynyl, arylalkoxycarbonyl, cyano, halogen, haloalkyl, haloalkoxy, nitro, sulfamyl, and xe2x80x94NRARB wherein RA and RB are as defined in formula I, and p is an integer of 1-2, may be prepared by treating heterocycles of general formula (47) with benzotriazole and aldehydes of general formula (26) in the presence of an acid catalyst such as p-toluenesulfonic acid monohydrate to provide benzotriazole adducts of general formula (48). Nucleophilic displacement of the benzotriazole moiety with guanidines of general formula (32) in a polar aprotic solvent such as N,N-dimethylformamide provides guanidine aminals of general formula (49). 
Aminals of general formula (52), wherein R1, R2, R3, R4, and R6 are as defined in formula I and X is selected from NCN, CHNO2, CHCN and C(CN)2, may be prepared as illustrated in Scheme 17. Bis(methylthio) compounds of general formula (50) are commercially available when X is NCN, CHNO2, or C(CN)2 or may be prepared as described in (Hendriksen, Acta Chem. Scand. (1990), 50, 432 and Creemer et al., Synth. Comm. (1988), 18, 1103) when X is CHCN. Compounds of general formula (50) may be treated with amines of general formula (5) to provide methylthio compounds of general formula (51). Methylthio compounds of general formula (51) may be treated with amines of general formula (10) to provide aminals of general formula (52) wherein X is NCN, CHNO2, CHCN, or C(CN)2. 
An alternate method of preparing aminals of general formula (52) wherein R1, R2, R3, R4, and R6 are as defined in formula I and X is selected from NCN, CHNO2, CHCN and C(CN)2 is shown in Scheme 18. Methylthio compounds of general formula (51) may be treated with ammonia in an alcoholic solvent such as methanol to provide compounds of general formula (53). Compounds of general formula (53) may be treated with benzotriazoles of general formula (27) to provide aminals of general formula (52) wherein X is NCN, CHNO2, CHCN or C(CN)2. 
Aminals of general formula (54), wherein R2, R3, and R6 are as defined in formula I and X is selected from NCN, CHNO2, CHCN and C(CN)2, may be prepared as illustrated in Scheme 19. Bis(methylthio) compounds of general formula (50) may be treated with heterocycles of general formula (43) to provide methylthio compounds of general formula (53). Methylthio compounds of general formula (53) may be treated with amines of general formula (10) to provide aminals of general formula (54) wherein X is NCN, CHNO2, CHCN or C(CN)2. 
Aminals of general formula (59), wherein R1, R2, R3, R4 and R6 are as defined in formula I, may be prepared as described in Scheme 20. Amines of general formula (5) may be treated with 1,1-bis(methylsulfanyl)-2-nitroethylene in a solvent such as isopropanol to provide nitroethenyl compounds of general formula (57). Nitroethenyl compounds of general formula (57) may be treated with ammonia and methanol to provide nitroethenediamines of general formula (58). Nitroethenediamines of general formula (58) may be treated with benzotriazole adducts of general formula (27) and a base such as potassium carbonate in a solvent such as DMF to provide aminals of general formula (59). 
Aminals of general formula (65), wherein R1, R2, R3 and R6 are as defined in formula I and R is selected from alkyl, aryl, haloalkyl and NR94R95 wherein R94 and R95 are independently selected from hydrogen, alkyl, aryl, and arylalkyl, may be prepared as described in Scheme 21. Isothiocyanates of general formula (61) may be treated with compounds of general formula (62) and sodium hydride followed by treatment with iodomethane in DMF to provide compounds of general formula (63). Compounds of general formula (63) may be treated with ammonia and methanol to provide guanidines of general formula (64). Guanidines of general formula (64) may be treated with benzotriazole adducts of general formula (27) and a base such as potassium carbonate in a solvent such as DMF to provide aminals of general formula (65). 
Aminals of general formula (70), wherein R1, R2, R3, R4 and R6 are as defined in formula I, may be prepared as described in Scheme 22. Amines of general formula (5) may be treated with cyanamide in water in the presence of a protic acid such as HCl to provide guanidines of general formula (68). Guanidines of general formula (68) may be treated with aqueous nitric acid to provide nitroguanidines of general formula (69). Nitroguanidines of general formula (69) may be treated with benzotriazole adducts of general formula (27) and a base such as potassium carbonate in a solvent such as DMF to provide aminals of general formula (70). 
Aminals of general formula (73), wherein R1, R2, R4, R5, R6 and R8 are as defined in formula I and Rxe2x80x2 is selected from alkoxycarbonyl, aryl, carboxy, heterocycle and xe2x80x94NRARB wherein RA and RB are as defined in formula I, may be prepared as described in Scheme 23. Aminals of general formula (72), wherein R is Br, I or xe2x80x94OS(O)2CF3, may be treated with a palladium catalyst, a trialkyltin reagent and triphenylarsine in a solvent such as N-methylpyrrolidin-2-one to provide aminals of general formula (73). Alternatively, cross-coupling reactions (and carbonylations) may be done using Buchwald, Stille, Suzuki or Heck coupling reactions all of which are well known to those skilled in the art of organic chemistry. 
Aminals of general formula (76), wherein R1 and R2 are as defined in formula (I) and Rxe2x80x2 is selected from alkoxycarbonyl, aryl, carboxy, heterocycle and xe2x80x94NRARB wherein RA and RB are as defined in formula (I), may be prepared as described in Scheme 24. Aminals of general formula (75), wherein R is Br, I or xe2x80x94OS(O)2CF3, may be treated with a palladium catalyst, a trialkyltin reagent and triphenylarsine in a solvent such as N-methylpyrrolidin-2-one as described in Farina et al., J. Org. Chem. (1990), 55, 5833 to provide aminals of general formula (76). Alternatively, cross-coupling reactions and carbonylations may be done on aminals of general formula (75) using Buchwald, Stille, Suzuki or Heck coupling reaction conditions all of which are well known to those skilled in the art of organic chemistry. 
An alternative and more preferred method of preparing aminals of general formula (76), wherein R1 and R2 are as defined in formula (I) and Rxe2x80x2 is selected from alkoxycarbonyl, aryl, carboxy, heterocycle and xe2x80x94NRARB wherein RA and RB are as defined in formula (I), is described in Scheme 25. Benzotriazole compounds of general formula (79), wherein R is Br, I or xe2x80x94OS(O)2CF3, may be treated with a palladium catalyst, a trialkyltin reagent and triphenylarsine in a solvent such as N-methylpyrrolidin-2-one as described in Farina et al., J. Org. Chem. (1990), 55, 5833 to provide elaborated benzotriazoles general formula (80). Alternatively, cross-coupling reactions and carbonylations may be done on benzotriazoles of general formula (80) using Buchwald, Stille, Suzuki or Heck coupling reaction conditions all of which are well known to those skilled in the art of organic chemistry. Benzotriazoles of general formula (80) may be treated with cyanoguanidines of general formula (28) in a polar, aprotic solvent such as DMF in the presence of a base such as cesium carbonate to provide aminals of general formula (76).
The compounds and processes of the present invention will be better understood by reference to the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention.